Novel substituted benzimidazole derivatives as d-amino acid oxidase (daao) inhibitors

ABSTRACT

The present invention provides novel substituted benzimidazole derivatives used as DAAO inhibitors and for treatment and/or prevention of neurological disorders.

CROSS-REFERENCE TO RELATED APPLICATION

This application is a continuation of U.S. application Ser. No.16/332,628, filed Mar. 12, 2019, which was a 371 National Stage Entry ofInternational Application No. PCT/US2017/051610, filed Sep. 14, 2017,which claims the benefit of U.S. Provisional Application No. 62/394,479,filed on Sep. 14, 2016, which are all incorporated herein by referencein their entirety.

FIELD OF THE INVENTION

The invention relates to D-amino acid oxidase (DAAO) inhibitors.Particularly, the present invention provides novel substitutedbenzimidazole derivatives used as DAAO inhibitors and for treatmentand/or prevention of neurological disorders.

BACKGROUND OF THE INVENTION

The aberrant regulatory mechanism of glutamate transmission onN-methyl-D-aspartic acid (NMDA) receptor has been reported as one of theneuropathology in schizophrenia. The receptor is a heterotetramercomposed of two structure subunits of NMDA receptor 1 (NR1) and NR2.Modulation of the glycine binding site of NMDA receptor may improve thecognitive function and negative symptoms in schizophrenia. D-amino acidoxidase (DAAO) was found to be involved in the activation process of theNMDA receptor. The substrates of DAAO, especially the D-serine, may bindto the glycine site of the NMDA receptor as a co-agonist. This in turnmay regulate the NMDA receptor in opening its calcium channel D-serinehas been found to inhibit the a-amino-3-hydroxy-5-methyl-4-isoxazolepropionic acid (AMPA) receptor-mediated current in rat hippocampusneurons.

Accordingly, there is a need to develop candidate drugs having DAAOinhibitory effect to treat various neurological and physical disorder.

SUMMARY OF THE INVENTION

The present invention pertains to a list of substituted benzimidazolederivatives used as DAAO inhibitors and for treatment and/or preventionof neurological disorders.

The present invention provides a compound having the following formula(I), wherein each substituent is described herein.

The present invention also provides a pharmaceutical compositioncomprising a compound of the present invention.

The present invention also provides a method of inhibiting a DAAOcomprising contacting a cell with a compound of the present invention.

The present invention also provides a method of treating or preventingthe disease associated with DAAO dysregulation in a subject comprisingadministrating an effective amount of a compound of the presentinvention to the subject.

In some embodiments, the disease is symptom domains of schizophrenia andschizoaffective disorder, depression, Tourette Syndrome, Post-traumaticstress disorder (PTSD), Obsessive-compulsive disorder (OCD), analgesics,loss of memory and/or cognition associated with neurodegenerativediseases or loss of neuronal function characteristic ofneurodegenerative diseases. Certain embodiments include mild cognitiveimpairment (MCI), Alzheimer's disease, Parkinson's disease andschizophrenia.

BRIEF DESCRIPTION OF THE DRAWING

FIG. 1 shows that compared to the MK-801 group, different dosages ofRS-D7, Drug 12083 and Prodrug 28095 can rescue the MK-801-inducedhyperlocomotion.

FIG. 2 shows that different dosages of RS-D7, Drug 12083 and Prodrug28095 rescue the anhedonia after acute MK-801 injection.

FIG. 3 shows a significant reduction of PPI after acute MK-801injections.

DETAILED DESCRIPTION OF THE INVENTION

Accordingly, DAAO was hypothesized to be implicated in the pathogenesisof schizophrenia. As the NMDA receptor also involved in affectivedisorder, it is likely that inhibiting the DAAO may elevate the functionof NMDA and improve both the symptoms of schizophrenia and depressionaffective disorder.

Known inhibitors of DAAO include benzoic acid, pyrrole-2-carboxylicacids, and indole-2-carboxylic acids. Indole derivatives andparticularly certain indole-2-carboxylates have been described in theliterature for treatment of neurodegenerative disease and neurotoxicinjury. EP 396124 discloses indole-2-carboxylates and derivatives fortreatment or management of neurotoxic injury resulting from a CNSdisorder or traumatic event or in treatment or management of aneurodegenerative disease. U.S. Pat. Nos. 5,373,018; 5,374,649;5,686,461; 5,962,496 and 6,100,289 disclose treatment of neurotoxicinjury and neurodegenerative disease using indole derivatives. WO03/039540 disclose DAAO inhibitors, including indole-2-carboxylic acids,and methods of enhancing learning, memory and cognition as well asmethods for treating neurodegenerative disorders. Patent Application No.WO/2005/089753 discloses benzisoxazole analogs and methods of treatingmental disorders, such as Schizophrenia. WO/2015/168346 discloses a listof known known compounds as DAAO inhibitors.

As used herein and in the appended claims, the singular forms “a,”“and,” and “the” include plural referents unless the context clearlydictates otherwise. When ranges are used herein for physical properties,such as molecular weight, or chemical properties, such as chemicalformulae, all combinations and subcombinations of ranges and specificembodiments therein are intended to be included. The term “or” refers to“and/or” unless explicitly indicated to refer to alternatives only orunless the alternatives are mutually exclusive. The term “about” whenreferring to a number or a numerical range means that the number ornumerical range referred to is an approximation within experimentalvariability (or within statistical experimental error). The term“comprising” (and related terms such as “comprise” or “comprises” or“having” or “including”) is not intended to exclude that in othercertain embodiments, for example, an embodiment of any composition ofmatter, composition, method, or process, or the like, described herein,may “consist of” or “consist essentially of” the described features.

Definitions

“Alkyl” refers to a straight or branched hydrocarbon chain radicalconsisting solely of carbon and hydrogen atoms, containing nounsaturation, having from one to fifteen carbon atoms (e.g., C₁-C₁₅alkyl). In certain embodiments, an alkyl comprises one to thirteencarbon atoms (e.g., C₁-C₁₀ alkyl). In certain embodiments, an alkylcomprises one to eight carbon atoms (e.g., C₁-C₈ alkyl). In otherembodiments, an alkyl comprises one to five carbon atoms (e.g., C₁-C₆alkyl). In other embodiments, an alkyl comprises one to four carbonatoms (e.g., C₁-C₄ alkyl). In other embodiments, an alkyl comprises oneto three carbon atoms (e.g., C₁-C₃ alkyl). In other embodiments, analkyl comprises one to two carbon atoms (e.g., C₁-C₂ alkyl). In otherembodiments, an alkyl comprises one carbon atom (e.g., C₁ alkyl). Inother embodiments, an alkyl comprises five to fifteen carbon atoms(e.g., C₅-C₁₅ alkyl). In other embodiments, an alkyl comprises five toeight carbon atoms (e.g., C₅-C₈ alkyl). In other embodiments, an alkylcomprises two to five carbon atoms (e.g., C₂-C₅ alkyl). In otherembodiments, an alkyl comprises three to five carbon atoms (e.g., C₃-C₈alkyl). In other embodiments, the alkyl group is selected from methyl,ethyl, 1-propyl (n-propyl), 1-methylethyl (iso-propyl), 1-butyl(n-butyl), 1-methylpropyl (sec-butyl), 2-methylpropyl (iso-butyl),1,1-dimethylethyl (tert-butyl), 1-pentyl (n-pentyl). The alkyl isattached to the rest of the molecule by a single bond. Unlessspecifically stated otherwise in the specification, an alkyl group isoptionally substituted by one or more of substituents.

“Alkoxy” refers to a radical bonded through an oxygen atom of theformula —O-alkyl, where alkyl is an alkyl chain as defined above.

“Alkenyl” refers to a straight or branched hydrocarbon chain radicalgroup consisting solely of carbon and hydrogen atoms, containing atleast one carbon-carbon double bond, and having from two to twelvecarbon atoms. In certain embodiments, an alkenyl comprises two to eightcarbon atoms. In other embodiments, an alkenyl comprises two to fourcarbon atoms. The alkenyl is attached to the rest of the molecule by asingle bond, for example, ethenyl (i.e., vinyl), prop-1-enyl (i.e.,allyl), but-1-enyl, pent-1-enyl, penta-1,4-dienyl, and the like. Unlessspecifically stated otherwise in the specification, an alkenyl group isoptionally substituted by one or more of substituents.

“Alkynyl” refers to a straight or branched hydrocarbon chain radicalgroup consisting solely of carbon and hydrogen atoms, containing atleast one carbon-carbon triple bond, having from two to twelve carbonatoms. In certain embodiments, an alkynyl comprises two to eight carbonatoms. In other embodiments, an alkynyl has two to four carbon atoms.The alkynyl is attached to the rest of the molecule by a single bond,for example, ethynyl, propynyl, butynyl, pentynyl, hexynyl, and thelike. Unless specifically stated otherwise in the specification, analkynyl group is optionally substituted by one or more of substituents.

“Aryl” refers to a radical derived from an aromatic monocyclic ormulticyclic hydrocarbon ring system by removing a hydrogen atom from aring carbon atom. The aromatic monocyclic or multicyclic hydrocarbonring system contains only hydrogen and carbon from five to eighteencarbon atoms, where at least one of the rings in the ring system isfully unsaturated, i.e., it contains a cyclic, delocalized (4n+2)pi-electron system in accordance with the Huckel theory. The ring systemfrom which aryl groups are derived include, but are not limited to,groups such as benzene, fluorene, indane, indene, tetralin andnaphthalene. Unless stated otherwise specifically in the specification,the term “aryl” or the prefix “ar-” (such as in “aralkyl”) is meant toinclude aryl radicals optionally substituted by one or more substituentsindependently selected from alkyl, alkenyl, alkynyl, halo, fluoroalkyl,cyano, nitro, optionally substituted aryl, optionally substitutedaralkyl, optionally substituted aralkenyl, optionally substitutedaralkynyl, optionally substituted carbocyclyl, optionally substitutedcarbocyclylalkyl, optionally substituted heterocyclyl, optionallysubstituted heterocyclylalkyl, optionally substituted heteroaryl,optionally substituted heteroarylalkyl, —R^(b)——OR^(a),—R^(b)—OC(O)—R^(a), —R^(b)—OC(O)—OR^(a), —R^(b)—OC(O)—N(R^(a))₂,—R^(b)——N(R^(a))₂, —R^(b)—C(O)R^(a), —R^(b)—C(O)OR^(a),—R^(b)—C(O)N(R^(a))₂, —R^(b)—O—R—C(O)N(R^(a))₂,—R^(b)——N(R^(a))C(O)OR^(a), —R^(b)—N(R^(a)) C(O)R^(a),—R^(b)—N(R^(a))S(O)_(t)R^(a) (where t is 1 or 2), —R^(b)—S(O)_(t)OR^(a)(where t is 1 or 2), —R^(b)——S(O).sub_(t)R^(a) (where t is 1 or 2) and—R^(b)—S(O)_(t)N(R^(a))₂ (where t is 1 or 2), where each R^(a) isindependently hydrogen, alkyl, fluoroalkyl, cycloalkyl, cycloalkylalkyl,aryl (optionally substituted with one or more halo groups), aralkyl,heterocyclyl, heterocyclylalkyl, heteroaryl or heteroarylalkyl, eachR.sup.b is independently a direct bond or a straight or branchedalkylene or alkenylene chain, and R.sup.c is a straight or branchedalkylene or alkenylene chain, and where each of the above substituentsis unsubstituted unless otherwise indicated.

“Heteroaryl” refers to a radical derived from a 3- to 18-memberedaromatic ring radical that comprises two to seventeen carbon atoms andfrom one to six heteroatoms selected from nitrogen, oxygen and sulfur.As used herein, the heteroaryl radical may be a monocyclic, bicyclic,tricyclic or tetracyclic ring system, wherein at least one of the ringsin the ring system is fully unsaturated, i.e., it contains a cyclic,delocalized (4n+2) pi-electron system in accordance with the Huckeltheory. Heteroaryl includes fused or bridged ring systems. Theheteroatom(s) in the heteroaryl radical is optionally oxidized. One ormore nitrogen atoms, if present, are optionally quaternized. Theheteroaryl is attached to the rest of the molecule through any atom ofthe ring(s). Examples of heteroaryls include, but are not limited to,azepinyl, acridinyl, benzimidazolyl, benzindolyl, 1,3-benzodioxolyl,benzofuranyl, benzooxazolyl, benzo[d]thiazolyl, benzothiadiazolyl,benzo[b][1,4]dioxepinyl, benzo[b][1,4]oxazinyl, 1,4-benzodioxanyl,benzonaphthofuranyl, benzoxazolyl, benzodioxolyl, benzodioxinyl,benzopyranyl, benzopyranonyl, benzofuranyl, benzofuranonyl, benzothienyl(benzothiophenyl), benzothieno[3,2-d]pyrimidinyl, benzotriazolyl,benzo[4,6]imidazo[1,2-a]pyridinyl, carbazolyl, cinnolinyl,cyclopenta[d]pyrimidinyl,6,7-dihydro-5H-cyclopenta[4,5]thieno[2,3-d]pyrimidinyl,5,6-dihydrobenzo[h]quinazolinyl, 5,6-dihydrobenzo[h]cinnolinyl,6,7-dihydro-5H-benzo[6,7]cyclohepta[1,2-c]pyridazinyl, dibenzofuranyl,dibenzothiophenyl, furanyl, furanonyl, furo[3,2-c]pyridinyl,5,6,7,8,9,10-hexahydrocycloocta[d]pyrimidinyl,5,6,7,8,9,10-hexahydrocycloocta[d]pyridazinyl,5,6,7,8,9,10-hexahydrocycloocta[d]pyridinyl, isothiazolyl, imidazolyl,indazolyl, indolyl, indazolyl, isoindolyl, indolinyl, isoindolinyl,isoquinolyl, indolizinyl, isoxazolyl,5,8-methano-5,6,7,8-tetrahydroquinazolinyl, naphthyridinyl,1,6-naphthyridinonyl, oxadiazolyl, 2-oxoazepinyl, oxazolyl, oxiranyl,5,6,6a,7,8,9,10,10a-octahydrobenzo[h]quinazolinyl, 1-phenyl-1H-pyrrolyl,phenazinyl, phenothiazinyl, phenoxazinyl, phthalazinyl, pteridinyl,purinyl, pyrrolyl, pyrazolyl, pyrazolo[3,4-d]pyrimidinyl, pyridinyl,pyrido[3,2-d]pyrimidinyl, pyrido[3,4-d]pyrimidinyl, pyrazinyl,pyrimidinyl, pyridazinyl, pyrrolyl, quinazolinyl, quinoxalinyl,quinolinyl, isoquinolinyl, tetrahydroquinolinyl,5,6,7,8-tetrahydroquinazolinyl,5,6,7,8-tetrahydrobenzo[4,5]thieno[2,3-d]pyrimidinyl,6,7,8,9-tetrahydro-5H-cyclohepta[4,5]thieno[2,3-d]pyrimidinyl,5,6,7,8-tetrahydropyrido[4,5-c]pyridazinyl, thiazolyl, thiadiazolyl,triazolyl, tetrazolyl, triazinyl, thieno[2,3-d]pyrimidinyl,thieno[3,2-d]pyrimidinyl, thieno[2,3-c]pyridinyl, and thiophenyl (i.e.thienyl). Unless stated otherwise specifically in the specification, theterm “heteroaryl” is meant to include heteroaryl radicals as definedabove which are optionally substituted by one or more substituentsselected from alkyl, alkenyl, alkynyl, halo, fluoroalkyl, haloalkenyl,haloalkynyl, oxo, thioxo, cyano, nitro, optionally substituted aryl,optionally substituted aralkyl, optionally substituted aralkenyl,optionally substituted aralkynyl, optionally substituted carbocyclyl,optionally substituted carbocyclylalkyl, optionally substitutedheterocyclyl, optionally substituted heterocyclylalkyl, optionallysubstituted heteroaryl, optionally substituted heteroarylalkyl,—R^(b)——OR^(a), —R^(b)—OC(O)—R^(a), —R^(b)—OC(O)—OR^(a),—R^(b)—OC(O)—N(R^(a))₂, —R^(b)——N(R^(a))₂, —R^(b)—C(O)R^(a),—R^(b)—C(O)OR^(a), —R^(b)—C(O)N(R^(a))₂, —R^(b)—O—R—C(O)N(R^(a))₂,—R^(b)——N(R^(a))C(O)OR^(a), —R^(b)—N(R^(a)) C(O)R^(a),—R^(b)—N(R^(a))S(O)_(t)R^(a) (where t is 1 or 2), —R^(b)—S(O)_(t)OR^(a)(where t is 1 or 2), —R^(b)——S(O).sub_(t)R^(a) (where t is 1 or 2) and—R^(b)—S(O)_(t)N(R^(a))₂ (where t is 1 or 2), where each R^(a) isindependently hydrogen, alkyl, fluoroalkyl, cycloalkyl, cycloalkylalkyl,aryl, aralkyl, heterocyclyl, heterocyclylalkyl, heteroaryl orheteroarylalkyl, each R.sup.b is independently a direct bond or astraight or branched alkylene or alkenylene chain, and R.sup.c is astraight or branched alkylene or alkenylene chain, and where each of theabove substituents is unsubstituted unless otherwise indicated.

The term “pharmaceutically acceptable salt” refers to salts preparedfrom pharmaceutically acceptable non-toxic bases or acids includinginorganic or organic bases and inorganic or organic acids. Salts ofbasic compounds encompassed within the term “pharmaceutically acceptablesalt” refer to non-toxic salts of the compounds of this invention whichare generally prepared by reacting the free base with a suitable organicor inorganic acid. Representative salts of basic compounds of thepresent invention include, but are not limited to, the following:acetate, ascorbate, adipate, alginate, aspirate, benzenesulfonate,benzoate, bicarbonate, bisulfate, bitartrate, borate, bromide, butyrate,camphorate, camphorsulfonate, camsylate, carbonate, chloride,clavulanate, citrate, cyclopentane propionate, diethylacetic,digluconate, dihydrochloride, dodecylsulfanate, edetate, edisylate,estolate, esylate, ethanesulfonate, formic, fumarate, gluceptate,glucoheptanoate, gluconate, glutamate, glycerophosphate,glycollylarsanilate, hemisulfate, heptanoate, hexanoate,hexylresorcinate, hydrabamine, hydrobromide, hydrochloride,2-hydroxyethanesulfonate, hydroxynaphthoate, iodide, isonicotinic,isothionate, lactate, lactobionate, laurate, malate, maleate, mandelate,mesylate, methylbromide, methylnitrate, methylsulfate, methanesulfonate,mucate, 2-naphthalenesulfonate, napsylate, nicotinate, nitrate,N-methylglucamine ammonium salt, oleate, oxalate, pamoate (embonate),palmitate, pantothenate, pectinate, persulfate, phosphate/diphosphate,pimelic, phenylpropionic, polygalacturonate, propionate, salicylate,stearate, sulfate, subacetate, succinate, tannate, tartrate, teoclate,thiocyanate, tosylate, triethiodide, trifluoroacetate, undeconate,valerate and the like. Furthermore, where the compounds of the inventioncarry an acidic moiety, suitable pharmaceutically acceptable saltsthereof include, but are not limited to, salts derived from inorganicbases including aluminum, ammonium, calcium, copper, ferric, ferrous,lithium, magnesium, manganic, mangamous, potassium, sodium, zinc, andthe like. Also included are the ammonium, calcium, magnesium, potassium,and sodium salts. Salts derived from pharmaceutically acceptable organicnon-toxic bases include salts of primary, secondary, and tertiaryamines, cyclic amines, dicyclohexyl amines and basic ion-exchangeresins, such as arginine, betaine, caffeine, choline,N,N-dibenzylethylenediamine, diethylamine, 2-diethylaminoethanol,2-dimethylaminoethanol, ethanolamine, ethylamine, ethylenediamine,N-ethylmorpholine, N-ethylpiperidine, glucamine, glucosamine, histidine,hydrabamine, isopropylamine, lysine, methylglucamine, morpholine,piperazine, piperidine, polyamine resins, procaine, purines,theobromine, triethylamine, trimethylamine, tripropylamine,tromethamine, and the like. Also, included are the basicnitrogen-containing groups that may be quaternized with such agents aslower alkyl halides, such as methyl, ethyl, propyl, and butyl chloride,bromides and iodides; dialkyl sulfates like dimethyl, diethyl, dibutyl;and diamyl sulfates, long chain halides such as decyl, lauryl, myristyland stearyl chlorides, bromides and iodides, aralkyl halides like benzyland phenethyl bromides and others.

The term “subject” includes living organisms such as humans, monkeys,cows, sheep, horses, pigs, cattle, goats, dogs, cats, mice, rats,cultured cells, and transgenic species thereof. In a preferredembodiment, the subject is a human.

The term “administering” includes routes of administration which allowthe active ingredient of the invention to perform their intendedfunction.

The term “treat” or “treatment” refers to a method of reducing theeffects of a disease or condition. Treatment can also refer to a methodof reducing the underlying cause of the disease or condition itselfrather than just the symptoms. The treatment can be any reduction fromnative levels and can be, but is not limited to, the complete ablationof the disease, condition, or the symptoms of the disease or condition.

The term “prevent,” “prevention” or “preventing” means inhibition oraverting of symptoms associated with the target disease.

The phrase “therapeutically effective amount” refers to that amount of acompound, material, or composition comprising a compound of the presentinvention which is effective for producing a desired therapeutic effect,at a reasonable benefit/risk ratio applicable to any medical treatment.

The term “neurological disorder” refers to any undesirable condition ofthe central or peripheral nervous system of a mammal. The term“neurological disorder” includes neurodegenerative diseases (e g,Alzheimer's disease, Parkinson's disease and amyotrophic lateralsclerosis), neuropsychiatric diseases (e.g. schizophrenia and anxieties,such as general anxiety disorder). Exemplary neurological disordersinclude MLS (cerebellar ataxia), Huntington's disease, Down syndrome,multi-infarct dementia, status epilecticus, contusive injuries (e.g.spinal cord injury and head injury), viral infection inducedneurodegeneration, (e.g. AIDS, encephalopathies), epilepsy, benignforgetfulness, closed head injury, sleep disorders, depression (e.g.,bipolar disorder), dementias, movement disorders, psychoses, alcoholism,post-traumatic stress disorder and the like. “Neurological disorder”also includes any undesirable condition associated with the disorder.For instance, a method of treating a neurodegenerative disorder includesmethods of treating loss of memory and/or loss of cognition associatedwith a neurodegenerative disorder. Such method would also includetreating or preventing loss of neuronal function characteristic ofneurodegenerative disorder.

Compounds of the Present Invention

In one aspect, the present invention provides a compound of formula (I):

-   wherein n is 0 or 1,-   X is —S—, —S(═O)— or —NR_(n)—; wherein    -   R_(n) is H or

-   A is —CH, —CR_(c) or N;-   R_(a) is —C(═O)OR_(a1), —OR_(a2), —O—C(═O)R_(a3) or    —O—C(═O)-T-OR_(a4); wherein    -   R_(a1) is H or linear or branched C₁₋₁₅alkyl;    -   R_(a2) is H, linear or branched C₁₋₁₅alkyl, phosphonate,        diarylphosphonate or an O-protecting group;    -   R_(a3) and R_(a4) are independently a protecting group, linear        or branched C₁₋₁₅alkyl, linear or branched C₂₋₁₅alkenyl,        -T-C₃₋₁₀cycloalkyl, -T-NHR_(a3p), -T-C₃₋₁₀cycloalkenyl,        -T-C₆₋₁₀aryl, -T-C₅₋₁₀heteroaryl, -T-NH—C(═O)—O—C₁₋₁₀alkyl,        -T-adamantyl or —C₁₋₃alkylene-C₆₋₁₀aryl where the alkylene is        substituted with -T-NHR_(a3p);    -   R_(a3p) is H or an N-protecting group;-   R_(b) is H, linear or branched C₁₋₁₅alkyl, linear or branched    C₂₋₁₅alkenyl, C₁₋₃alkoxy-C₁₋₁₅alkyl-, -T′-C₃₋₁₀cycloalkyl,    -T′-C₃₋₁₀cycloalkenyl, -T′-C₆₋₁₀aryl or -T′-C₅₋₁₀heteroaryl;-   R_(c) each is independently linear or branched C₁₋₁₅alkyl, linear or    branched C₁₋₁₅alkoxyl, unprotected or protected hydroxyl group, or    —C₁₋₁₀alkylene-Y—C₆₋₁₀heteroaryl wherein —Y— is —CH₂—, —NH—, —O— or    —S—;-   symbol * represents the bonding position;-   m is an integer from 0 to 4;-   -T- is absent, C₁₋₃alkylene or C₂₋₃alkenylene;-   -T′- is C₁₋₃alkylene or C₂₋₃alkenylene; and-   wherein the heteroaryl contains at least one heteroatom, each    heteroatom being independently S, N or O;-   wherein the alkyl, alkenyl, alkoxy, cycloalkyl, aryl, heteroaryl,    alkylene and alkenylene are each independently unsubstituted or    substituted with at least one substituent;-   wherein the substituent is each independently a halogen, a    protecting group, protected or unprotected amino group, nitro,    nitroso, linear or branched C₁₋₁₅ alkyl, or linear or branched C₁₋₁₅    alkoxy or C₃₋₁₀cycloalkyl; and-   when R_(b) is H, the tautomers are included,-   with the proviso that-   when X is —S— or —S(═O)—, R^(a) is —OR_(a2) and R_(a2) is H or    linear or branched C₁₋₁₅alkyl, then A is —CH or —CR_(c);-   when X is —S— or —S(═O)— and R_(a) is —C(═O)OR_(a1), R_(b) is linear    or branched C₁₋₁₅alkyl, linear or branched C₆₋₁₅alkenyl,    C₁₋₃alkoxy-C₁₋₁₅alkyl-, T′-C₃₋₁₀cycloalkyl, T′-C₃₋₁₀cycloalkenyl,    -T′-C₆₋₁₀ aryl or -T′-C₅₋₁₀heteroaryl;-   or a pharmaceutically acceptable salt thereof.

In one embodiment, the present invention provides a compound of formula(I-a):

-   wherein n is 0 or 1,-   X is —S—, —S(═O)— or —NR_(n)—; wherein    -   R_(n), is H or

-   A is —CH, —CR_(c) or N;-   R_(a) is —C(═O)OR_(a1), —OR_(a2), —O—C(═O)R_(a3) or    —O—C(═O)-T-OR_(a4); wherein    -   R_(a1) is H or linear or branched C₁₋₁₅alkyl;    -   R_(a2) is H, linear or branched C₁₋₁₅alkyl, diarylphosphonate or        an O-protecting group;    -   R_(a3) and R_(a4) are independently a protecting group, linear        or branched C₁₋₁₅alkyl, linear or branched C₂₋₁₅alkenyl,        -T-C₃₋₁₀cycloalkyl, -T-NHR_(a3p), -T-C₃₋₁₀cycloalkenyl,        -T-C₆₋₁₀aryl, -T-C₅₋₁₀heteroaryl, -T-NH—C(═O)—O—C₁₋₁₀alkyl or        -T-adamantyl;    -   R_(a3p) is H or an N-protecting group;-   R_(b) is H, linear or branched C₁₋₁₅alkyl, linear or branched    C₂₋₁₅alkenyl, C₁₋₃alkoxy-C₁₋₁₅alkyl-, -T′-C₃₋₁₀cycloalkyl,    -T′-C₃₋₁₀cycloalkenyl, -T′-C₆₋₁₀ aryl or -T′-C₅₋₁₀heteroaryl;-   R_(c) each is independently linear or branched C₁₋₁₅alkyl, linear or    branched C₁₋₁₅alkoxyl, unprotected or protected hydroxyl group, or    —C₁₋₁₀alkylene-Y—C₆₋₁₀heteroaryl wherein —Y— is —CH₂—, —NH—, —O— or    —S—;-   symbol * represents the bonding position;-   m is an integer from 0 to 4;-   -T- is absent, C₁₋₃alkylene or C₂₋₃alkenylene;-   -T′- is C₁₋₃alkylene or C₂₋₃alkenylene; and-   wherein the heteroaryl contains at least one heteroatom, each    heteroatom being independently S, N or O;-   wherein the alkyl, alkenyl, alkoxy, cycloalkyl, aryl, heteroaryl,    alkylene and alkenylene are each independently unsubstituted or    substituted with at least one substituent;-   wherein the substituent is each independently a halogen, a    protecting group, protected or unprotected amino group, nitro,    nitroso, linear or branched C₁₋₁₅ alkyl, linear or branched C₁₋₁₅    alkoxy or C₃₋₁₀cycloalkyl and-   when R_(b) is H, the tautomers are included,-   with the proviso that-   when X is —S— or —S(═O)—, R_(a) is —OR_(a2) and R_(a2) is H or    linear or branched C₁₋₁₅alkyl, then A is —CH or —CR_(c);-   when X is —S— or —S(═O)— and R_(a) is —C(═O)OR_(a1), R_(b) is linear    or branched C₆₋₁₅alkyl, linear or branched C₆₋₁₅alkenyl,    C₁₋₃alkoxy-C₁₋₁₅alkyl-, -T′-C₃₋₁₀cycloalkyl, -T′-C₃₋₁₀cycloalkenyl,    -T′-C₆₋₁₀ aryl or -T′-C₅₋₁₀heteroaryl;-   or a pharmaceutically acceptable salt thereof.

In one embodiment, the present invention provides a compound of formula(I-b),

-   wherein n is 0 or 1,-   X is —S—, —S(═O)— or —NR_(n)—;    -   Rn is H or

-   A is —CH, —CR_(c) or N;-   R_(a) is —C(═O)OR_(a1), —OR_(a2) or —O—C(═O)R_(a3); wherein    -   R_(a1) is H or linear or branched C₁₋₁₅alkyl;    -   R_(a2) is H, linear or branched C₁₋₁₅alkyl, phosphonate,        diarylphosphonate or an O— protecting group;    -   R_(a3) is -T-NHR_(a3p), -T-NH—C(═O)—O—C₁₋₁₀alkyl or        —C₁₋₃alkylene-C₆₋₁₀aryl where the alkylene is substituted with        -T-NHR_(a3p);    -   R_(a3p) is H or an N-protecting group;-   R_(b) is H, linear or branched C₁₋₁₅alkyl, C₁₋₃alkoxy-C₁₋₁₀alkyl-,    -T′-C₃₋₁₀ cycloalkyl, -T′-C₃₋₁₀cycloalkenyl, -T′-C₆₋₁₀ aryl or    -T′-C₅₋₁₀ heteroaryl;-   R_(c) each is independently linear or branched C₁₋₁₅alkyl, linear or    branched C₁₋₁₅alkoxyl, unprotected or protected hydroxyl group or    —C₁₋₁₀alkylene-Y—C₆₋₁₀heteroaryl wherein —Y— is —CH₂—, —NH—, —O— or    —S—;-   symbol * represents the bonding position;-   m is an integer from 0 to 4;-   -T- is absent, C₁₋₃alkylene or C₂₋₃alkenylene;-   -T′- is C₁₋₃alkylene; and-   wherein the heteroaryl contains at least one heteroatom, each    heteroatom being independently S, N or O;-   wherein the alkyl, alkenyl, alkoxy, cycloalkyl, aryl and heteroaryl    are each independently unsubstituted or substituted with at least    one substituent;-   wherein the substituent is each independently a halogen, protected    or unprotected amino group, nitro, nitroso, linear or branched C₁₋₁₅    alkyl, linear or branched C₁₋₁₅ alkoxy or C₃₋₁₀cycloalkyl; and-   when R_(b) is H, the tautomers are included,-   with the proviso that-   when X is —S— or —S(═O)—, R_(a) is —OR_(a2) and R_(a2) is H or    linear or branched C₁₋₁₅alkyl, then A is—CH or —CRc;-   when X is —S— or —S(═O)— and R_(a) is —C(═O)OR_(a1), R_(b) is linear    or branched C₆₋₁₅alkyl, linear or branched C₆₋₁₅alkenyl,    C₁₋₃alkoxy-C₁₋₁₅alkyl-, -T′-C₃₋₁₀cycloalkyl, -T′-C₃₋₁₀ cycloalkenyl,    -T′-C₆₋₁₀ aryl or -T-C₅₋₁₀heteroaryl;-   or a pharmaceutically acceptable salt thereof.

In one embodiment, the present invention provides the compound offormula (I), wherein n is 0 or 1;

-   X is —S—, —S(═O)— or —NR—; wherein-   R_(n) is H or

-   A is —CH, —CR_(c) or N;-   R_(a) is —OR_(a2), —O—C(═O)R_(a3) or —O—C(═O)-T-OR_(a4); wherein-   R_(a2) is H, linear or branched C₁₋₁₅alkyl, phosphonate,    diarylphosphonate or an O-protecting group;-   R_(a3) and R_(a4) are independently a protecting group, linear or    branched C₁₋₁₅alkyl, linear or branched C₂₋₁₅alkenyl,    -T-C₃₋₁₀cycloalkyl, -T-NHR_(a3p), -T-C₃₋₁₀cycloalkenyl,    -T-C₆₋₁₀aryl, -T-C₅₋₁₀heteroaryl, -T-NH—C(═O)—O—C₁₋₁₀alkyl,    -T-adamantyl or —C₁₋₃alkylene-C₆₋₁₀aryl where the alkylene is    substituted with -T-NHR_(a3p);-   R_(a3p) is H or an N-protecting group;-   R_(b) is H, linear or branched C₁₋₁₅alkyl, linear or branched    C₂₋₁₅alkenyl, C₁₋₃alkoxy-C₁₋₃alkyl-, -T′-C₃₋₁₀cycloalkyl,    -T′-C₃₋₁₀cycloalkenyl, -T′-C₆₋₁₀ aryl or -T′-C₅₋₁₀heteroaryl;-   R_(c) each is independently linear or branched C₁₋₁₅alkyl, linear or    branched C₁₋₁₅alkoxyl, unprotected or protected hydroxyl group, or    —C₁₋₁₀alkylene-Y−C₆₋₁₀heteroaryl wherein —Y— is —CH₂—, —NH—, —O— or    —S—;-   symbol * represents the bonding position;-   m is an integer from 0 to 4;-   -T- is absent, C₁₋₃alkylene or C₂₋₃alkenylene;-   -T′- is C₁₋₃alkylene or C₂₋₃alkenylene; and-   wherein the heteroaryl contains at least one heteroatom, each    heteroatom being independently S, N or O;-   wherein the alkyl, alkenyl, alkoxy, cycloalkyl, aryl, heteroaryl,    alkylene and alkenylene are each independently unsubstituted or    substituted with at least one substituent;-   wherein the substituent is each independently a halogen, a    protecting group, protected or unprotected amino group, nitro,    nitroso, linear or branched C₁₋₁₅ alkyl, or linear or branched C₁₋₁₅    alkoxy or C₃₋₁₀cycloalkyl; and-   when R_(b) is H, the tautomers are included,-   with the proviso that-   when X is —S— or —S(═O)—, R_(a) is —OR_(a2) and R_(a2) is H or    linear or branched C₁₋₁₅alkyl, then A is —CH or —CR_(c);-   or a pharmaceutically acceptable salt thereof.

In a further embodiment, the present invention provides the compound offormula (I), wherein

-   n is 0;    -   X is —S(═O)—;    -   A is N;    -   R_(a) is —OR_(a2), —O—C(═O)R_(a3) or —O—C(═O)-T-OR_(a4), wherein        R_(a2) is H, linear or branched C₁₋₁₅alkyl, phosphonate,        diarylphosphonate or an O-protecting group;    -   R_(a3) and R_(a4) are independently a protecting group, linear        or branched C₁₋₁₅alkyl, linear or branched C₂₋₁₅alkenyl,        -T-C₃₋₁₀cycloalkyl, -T-NHR_(a3p), -T-C₃₋₁₀cycloalkenyl,        -T-C₆₋₁₀aryl, -T-C₅₋₁₀heteroaryl, -T-NH—C(═O)—O—C₁₋₁₀alkyl,        -T-adamantyl or —C₁₋₃alkylene-C₆₋₁₀aryl where the alkylene is        substituted with -T-NHR_(a3p); R_(a3p) is H or an N-protecting        group;    -   R_(b) is H;    -   m is 3; and    -   R_(c) each is independently linear or branched C₁₋₁₅alkyl,        linear or branched C₁₋₁₅alkoxyl;

or a pharmaceutically acceptable salt thereof.

In one embodiment, n is 0.

In one embodiment, m is an integer from 0 to 3.

In some embodiments, R_(a) is —C(═O)OH, —C(═O)OC₁₋₄alkyl, H, —OR_(a2)wherein R_(a2) is H, linear or branched C₁₋₁₀alkyl or an O-protectinggroup; —O—C(═O)R_(a3)wherein R_(a3) is independently tert-butylprotecting group; linear or branched C₁₋₁₀alkyl unsubstituted orsubstituted by halogen, tert-butyl protecting group or protected aminogroup; linear or branched C₂₋₁₀alkenyl; C₁₋₄alkoxy; C₃₋₁₀cycloalkyl;—C₁₋₃alkylene-C₃₋₁₀cycloalkyl; —C₃₋₁₀cycloalkenyl; —C₆₋₁₀arylunsubstituted or substituted by C₁₋₁₀ alkyl, nitro, C₁₋₁₅alkoxy orhalogen; —C₅₋₁₀heteroaryl unsubstituted or substituted by C₁₋₁₀alkoxy;C₂₋₃alkenylene-C₆₋₁₀aryl wherein C₆₋₁₀aryl is unsubstituted orsubstituted by halogen; —C₁₋₃alkylene-NH——C(═O)—O—C₁₋₁₀alkyl; oradamantly; or —O—C(═O)—O—C₁₋₁₀alkyl.

In some embodiments, R_(a) is —O—C₁₋₁₀alkyl; —O-protecting group or—O—C(═O)R_(a3) wherein R_(a3) is a tert-butyl protecting group;adamantly; linear or branched C₁₋₁₀alkyl unsubstituted or substituted byhalogen or a tert-butyl protecting group; C₁₋₄alkoxy; —C₆₋₁₀arylunsubstituted or substituted by C₁₋₁₀ alkyl, nitro, C₁₋₁₅alkoxy orhalogen; C₃₋₁₀cycloalkyl; —C₃₋₁₀cycloalkenyl; linear or branchedC₂₋₁₀alkenyl; —C₅₋₁₀heteroaryl; —C₁₋₃alkylene-C₃₋₁₀cycloalkyl;C₂₋₃alkenylene-C₆₋₁₀aryl wherein C₆₋₁₀aryl is unsubstituted orsubstituted by halogen; —O—C(═O)—O—C₁₋₁₀alkyl. In some embodiments,R_(a) is —O—C₁₋₄alkyl, —O-tert-butyloxycarbonyl protecting group or—O—C(═O)R_(a3) wherein R_(a3) is a tert-butyl protecting group;adamantly; linear or branched C₁₋₈alkyl unsubstituted or substituted byhalogen or a tert-butyl protecting group; C₁₋₄alkoxy; -phenylunsubstituted or substituted by C₁₋₆ alkyl, nitro, C₁₋₄alkoxy orhalogen; C₃₋₆cycloalkyl; —C₃₋₆cycloalkenyl; linear or branchedC₂₋₆alkenyl; —C₅₋₆heteroaryl; —C₁₋₃alkylene-C₃₋₆cycloalkyl;C₂₋₃alkenylene-phenyl wherein phenyl is unsubstituted or substituted byhalogen; —O—C(═O)—O—C₁₋₄alkyl. In some further embodiments,C₃₋₆cycloalkyl is cyclopropyl or cyclohexyl. In some furtherembodiments, —C₃₋₁₀cycloalkenyl is cyclohexenyl.

In some further embodiments, heteroaryl is pyrrolidinyl, pyrrolinyl,pyrazolidinyl, imidazolidinyl, pyrazolinyl, imidazolinyl, pyrazolyl,imidazolyl, tetrahydrofuranyl, furanyl, dioxolanyl,tetrahydrothiophenyl, thiophenyl, oxazolyl, isoxazolyl, isothiazolyl,thiazolyl, oxathiolanyl, piperidinyl, pyridinyl, piperazinyl,pyridazinyl, pyrimidinyl, pyrazinyl, tetrahydropyranyl, pyranyl,dioxanyl, thianyl, thiopyranyl, morpholinyl, oxazinyl or thiazinyl. Infurther embodiments, heteroaryl is furanyl, isoxazolyl or thiophenyl.

In some embodiments, R^(a) is —OH, —COOH, —O-phosphate, —O—C₁₋₆alkyl or—O—C(═O)—C₁₋₆alkyl, —O—C(═O)—C₁₋₄alkylene-NH(Fmoc or Bocprotectinggroup), or —O—C(═O)—NH—C(═O)—O—C₁₋₁₀alkyl.

In some embodiments, R_(c) each is independently linear or branchedC₁₋₆alkyl or linear or branched C₁₋₆alkoxyl. In some embodiments, R_(c)each is independently halogen, linear or branched C₁₋₆alkyl, linear orbranched C₁₋₆alkoxyl, or —C₁₋₁₀alkenylene-Y—C₆₋₁₀heteroaryl; wherein Yis S and C₆₋₁₀heteroaryl is unsubstituted or substituted by C₁₋₁₅alkyl(preferably C₁₋₄alkyl), C₁₋₁₅alkenyl (preferably C₂₋₄alkyl), C₁₋₁₅alkoxy(preferably C₁₋₄alkoxy), —OH, —NH₂, —NO₂ or halogen. In a furtherembodiment, —C₁₋₁₀alkenylene-Y—C₆₋₁₀heteroaryl is

In some embodiments, the compound of the present invention is selectedfrom the group consisting of:

NCTU-SUN- ID M.W. Chemical Structure 13001 488.56

26090 410.52

21115 398.46

25030 429.17

28096 479.55

12093 472.56

25016 415.16

12130 508.43

27077 401.48

27079 449.52

26089 420.47

21129 453.12

25032 403.12

26098 491.61

21127 449.14

25017 480.11

12128 455.18

26071 460.53

11021 453.12

21118 444.22

26070 406.44

25029 415.16

12129 495.98

11023 426.10

26096 401.48

25027 413.14

28092 399.13

12088 469.64

12127 415.5

21117 434.54

12084 481.61

21126 480.11

26097 441.55

21110 412.49

21116 448.57

21120 517.27

21121 579.28

22138 328.43

25015 415.16

28094 449.52

28091 480.11

21130 413.14

21103 412.49

21122 373.11

11022 493.62

11030 491.61

21102 368.44

21132 431.15

12123 385.44

13084 563.56

12094 670.78

21105 583.73

12124 399.46

12122 425.46

26072 583.69

22140 506.14

21133 506.11

21125 469.09

27078 439.53

11020 465.13

26076 396.49

25031 403.12

21128 443.19

27076 429.53

12083 451.58

21119 430.20

21104 547.65

21106 462.59

26077 446.51

26066 410.52

12125 413.49

26065 420.46

26079 434.50

25028 441.08

26092 474.56

21124 435.13

28093 429.53

26091 424.55

22139 344.11

22141 314.1

28087 449.14

21123 387.13

12092 594.69

21098 382.46

21131 421.09

12082 465.61

28095 471.61

11031 487.93

or a pharmaceutically acceptable salt thereof.

The present invention encompasses all stereoisomeric forms of thecompounds of Formula I, Formula I-a and Formula I-b. Centers ofasymmetry that are present in the compounds of Formula I, Formula I-aand Formula I-b can all independently of one another have (R)configuration or (S) configuration. When bonds to the chiral carbon aredepicted as straight lines in the structural Formulas of the invention,it is understood that both the (R) and (S) configurations of the chiralcarbon, and hence both enantiomers and mixtures thereof, are embracedwithin the Formula. When a particular configuration is depicted, thatentantiomer (either (R) or (S), at that center) is intended. Similarly,when a compound name is recited without a chiral designation for achiral carbon, it is understood that both the (R) and (S) configurationsof the chiral carbon, and hence individual enantiomers and mixturesthereof, are embraced by the name

The invention includes all possible enantiomers and diastereomers andmixtures of two or more stereoisomers, for example mixtures ofenantiomers and/or diastereomers, in all ratios. Thus, enantiomers are asubject of the invention in enantiomerically pure form, both aslevorotatory and as dextrorotatory antipodes, in the form of racematesand in the form of mixtures of the two enantiomers in all ratios. In thecase of a cis/trans isomerism the invention includes both the cis formand the trans form as well as mixtures of these forms in all ratios. Thepreparation of individual stereoisomers can be carried out, if desired,by separation of a mixture by customary methods, for example bychromatography or crystallization, by the use of stereochemicallyuniform starting materials for the synthesis or by stereoselectivesynthesis. Optionally a derivatization can be carried out before aseparation of stereoisomers. The separation of a mixture ofstereoisomers can be carried out at an intermediate step during thesynthesis of a compound of Formula I, Formula I-a and Formula I-b or itcan be done on a final racemic product. Absolute stereochemistry may bedetermined by X-ray crystallography of crystalline products orcrystalline intermediates which are derivatized, if necessary, with areagent containing a stereogenic center of known configuration. Wherecompounds of this invention are capable of tautomerization, allindividual tautomers as well as mixtures thereof are included in thescope of this invention. The present invention includes all suchisomers, as well as salts, solvates (including hydrates) and solvatedsalts of such racemates, enantiomers, diastereomers and tautomers andmixtures thereof.

General Preparation Procedures of the Compounds of the Present Invention

The compounds of Formula (I) of the present invention are preparedaccording to general chemical synthetic procedures. The preparation ofthe embodiments of the compounds of the present invention is illustratedbelow.

Synthetic Scheme and Procedure for the Preparation of the Compounds ofthe Invention from RS-D7

-   R is —R_(a3) or -T-OR_(a4).

Synthetic Scheme and Procedure for the Preparation of NCTU-SUN-26065Series

Synthetic Scheme and Procedure for the Preparation of NCTU-SUN-26070Series

Synthetic Scheme and Procedure for the Preparation of NCTU-SUN-26079Series

Synthetic Scheme and Procedure for the Preparation of NCTU-SUN-26089Series

Synthetic Scheme and Procedure for the Preparation of NCTU-SUN-12082Series

Synthetic Scheme and Procedure for the Preparation of NCTU-SUN-12083Series

Synthetic Scheme and Procedure for the Preparation of NCTU-SUN-12084

Synthetic Scheme and Procedure for the Preparation of NCTU-SUN-12092Series

Synthetic Scheme and Procedure for the Preparation of NCTU-SUN-22138Series

Synthetic Scheme and Procedure for the Preparation of NCTU-SUN-22139

Utilities

The compounds of the invention are useful for treating or preventing anydisease and/or condition, wherein modulation of D-serine levels, and/orits oxidative products, is effective in ameliorating symptoms.Inhibition of the enzyme can lead to increases in D-serine levels and areduction in the formation of toxic D-serine oxidation products. Thus,the invention provides methods for the treatment or prevention ofneurological disorders and methods of enhancing learning, memory and/orcognition. The invention also provides methods for the treatment orprevention of the disease mediated by DAAO inhibition; preferably,symptom domains of schizophrenia and schizoaffective disorder,depression, Tourette Syndrome, Post-traumatic stress disorder (PTSD),Obsessive-compulsive disorder (OCD), analgesics, loss of memory and/orcognition associated with neurodegenerative diseases or loss of neuronalfunction characteristic of neurodegenerative diseases. In someembodiments, the symptom domains of schizophrenia and schizoaffectivedisorder include negative, cognitive, depressive, positive and generalpsychopathology symptom domains. In another embodiment, the diseaseassociated with DAAO inhibition is mild cognitive impairment (MCI),Alzheimer's disease, Parkinson's disease or schizophrenia. In someembodiments, the disease associated with DAAO inhibition is pain, ataxiaor convulsion. In some embodiments, the compounds of the invention canbe used for treating or preventing loss of memory and/or cognitionassociated with neurodegenerative diseases (e.g., Alzheimer's diseaseand schizophrenia) and for preventing loss of neuronal functioncharacteristic of neurodegenerative diseases. Further, methods areprovided for the treatment or prevention of pain, ataxia and convulsion.

In some embodiment, the effective amount of the compound describedherein ranges from about 0.5 mg/kg body weight to about 20 g/kg, about 1mg/kg body weight to about 20 g/kg, about 2 mg/kg body weight to about20 g/kg, about 4 mg/kg body weight to about 20 g/kg, about 6 mg/kg bodyweight to about 20 g/kg, about 8 mg/kg body weight to about 20 g/kg,about 10 mg/kg body weight to about 20 g/kg, about 12 mg/kg body weightto about 20 g/kg, about 14 mg/kg body weight to about 20 g/kg, about 16mg/kg body weight to about 20 g/kg, about 0.5 mg/kg body weight to about15 g/kg, about 0.5 mg/kg body weight to about 12 g/kg, about 0.5 mg/kgbody weight to about 10 g/kg, about 0.5 mg/kg body weight to about 8g/kg, about 0.5 mg/kg body weight to about 6 g/kg, about 2 mg/kg bodyweight to about 15 g/kg, about 2 mg/kg body weight to about 12 g/kg,about 2 mg/kg body weight to about 10 g/kg, about 2 mg/kg body weight toabout 7 g/kg, about 2 mg/kg body weight to about 5 g/kg, about 5 mg/kgbody weight to about 15 g/kg or about 5 mg/kg body weight to about 10g/kg body weight.

Pharmaceutical Composition

Another aspect of the present invention provides pharmaceuticalcompositions which comprises a compound of Formula I (or apharmaceutically acceptable salt or solvate thereof) and apharmaceutically acceptable carrier. The term “composition”, as inpharmaceutical composition, is intended to encompass a productcomprising the active ingredient(s), and the inert ingredient(s)(pharmaceutically acceptable excipients) that make up the carrier, aswell as any product which results, directly or indirectly, fromcombination, complexation or aggregation of any two or more of theingredients, or from dissociation of one or more of the ingredients, orfrom other types of reactions or interactions of one or more of theingredients. Accordingly, the pharmaceutical compositions of the presentinvention encompass any composition made by admixing a compound ofFormula I, additional active ingredient(s), and pharmaceuticallyacceptable excipients.

The pharmaceutical compositions of the present invention comprise acompound represented by Formula I (or a pharmaceutically acceptable saltor solvate thereof) as an active ingredient, a pharmaceuticallyacceptable carrier and optionally other therapeutic ingredients oradjuvants. The compositions include compositions suitable for oral,rectal, topical, and parenteral (including subcutaneous, intramuscular,and intravenous) administration, although the most suitable route in anygiven case will depend on the particular host, and nature and severityof the conditions for which the active ingredient is being administered.The pharmaceutical compositions may be conveniently presented in unitdosage form and prepared by any of the methods well known in the art ofpharmacy.

The active ingredient can be administered orally in solid dosage forms,such as capsules, tablets, troches, dragees, granules and powders, or inliquid dosage forms, such as elixirs, syrups, emulsions, dispersions,and suspensions. The active ingredient can also be administeredparenterally, in sterile liquid dosage forms, such as dispersions,suspensions or solutions. Other dosages forms that can also be used toadminister the active ingredient as an ointment, cream, drops,transdermal patch or powder for topical administration, as an ophthalmicsolution or suspension formation, i.e., eye drops, for ocularadministration, as an aerosol spray or powder composition for inhalationor intranasal administration, or as a cream, ointment, spray orsuppository for rectal or vaginal administration.

For topical applications, the active ingredient or a pharmaceuticalcomposition thereof can be formulated in a suitable ointment containingthe active component suspended or dissolved in one or more carriers.Carriers for topical administration of the active ingredient or apharmaceutical composition thereof include, but are not limited to,mineral oil, liquid petrolatum, white petrolatum, propylene glycol,polyoxyethylene, polyoxypropylene compound, emulsifying wax, sugars suchas lactose and water. Alternatively, the pharmaceutical compositions canbe formulated in a suitable lotion or cream containing the activeingredient or a pharmaceutical composition thereof suspended ordissolved in one or more pharmaceutically acceptable carriers. Suitablecarriers include, but are not limited to, mineral oil, sorbitanmonostearate, polysorbate 60, cetyl esters wax, cetearyl alcohol,2-octyldodecanol, benzyl alcohol and water.

Depending on the particular condition, disorder or disease to betreated, additional therapeutic agents can be administered together withthe active ingredient or a pharmaceutical composition thereof. Thoseadditional agents can be administered sequentially in any order, as partof a multiple dosage regimen, from the active ingredient or apharmaceutical composition thereof (consecutive or intermittentadministration). Alternatively, those agents can be part of a singledosage form, mixed together with the active ingredient or apharmaceutical composition thereof (simultaneous or concurrentadministration).

For oral administration, a pharmaceutical composition useful in theinvention can take the form of solutions, suspensions, tablets, pills,capsules, powders, granules, semisolids, sustained release formulations,elixirs, aerosols, and the like. Tablets containing various excipientssuch as sodium citrate, calcium carbonate and calcium phosphate areemployed along with various disintegrants such as starch, preferablypotato or tapioca starch, and certain complex silicates, together withbinding agents such as polyvinylpyrrolidone, sucrose, gelatin andacacia. Additionally, lubricating agents such as magnesium stearate,sodium lauryl sulfate and talc are often very useful for tablettingpurposes. Solid compositions of a similar type are also employed asfillers in soft and hard-filled gelatin capsules; preferred materials inthis connection also include lactose or milk sugar as well as highmolecular weight polyethylene glycols. When aqueous suspensions and/orelixirs are desired for oral administration, t the active ingredient ora pharmaceutical composition thereof of this invention can be combinedwith various sweetening agents, flavoring agents, coloring agents,emulsifying agents and/or suspending agents, as well as such diluents aswater, ethanol, propylene glycol, glycerin and various like combinationsthereof.

The term “parenteral” as used herein refers to modes of administrationwhich include intravenous, intramuscular, intraperitoneal, intrasternal,subcutaneous, intramedullary and intraarticular injection and infusion.A pharmaceutical composition for parenteral injection can comprisepharmaceutically acceptable sterile aqueous or nonaqueous solutions,dispersions, suspensions or emulsions as well as sterile powders forreconstitution into sterile injectable solutions or dispersions justprior to use. Aqueous solutions are especially suitable for intravenous,intramuscular, subcutaneous and intraperitoneal injection purposes. Inthis connection, the sterile aqueous media employed are all readilyobtainable by standard techniques well-known to those skilled in theart. Examples of suitable aqueous and nonaqueous carriers, diluents,solvents or vehicles include water, ethanol, polyols (such as glycerol,propylene glycol, polyethylene glycol, and the like),carboxymethylcellulose and suitable mixtures thereof, vegetable oils(such as olive oil), and injectable organic esters such as ethyl oleate.Proper fluidity can be maintained, for example, by the use of coatingmaterials such as lecithin, by the maintenance of the required particlesize in the case of dispersions, and by the use of surfactants.

The pharmaceutical compositions useful in the present invention can alsocontain adjuvants such as, but not limited to, preservatives, wettingagents, emulsifying agents, and dispersing agents. Prevention of theaction of microorganisms can be ensured by the inclusion of variousantibacterial and antifungal agents, such as for example, paraben,chlorobutanol, phenol sorbic acid, and the like. It can also bedesirable to include isotonic agents such as sugars, sodium chloride,and the like. Prolonged absorption of the injectable pharmaceutical formcan be brought about by the inclusion of agents that delay absorptionsuch as aluminum monostearate and gelatin.

Administration by slow infusion is particularly useful when intrathecalor epidural routes are employed. A number of implantable orbody-mountable pumps useful in delivering compound at a regulated rateare known in the art.

Suspensions, in addition to the active compounds, can contain suspendingagents as, for example, ethoxylated isostearyl alcohols, polyoxyethylenesorbitol and sorbitan esters, microcrystalline cellulose, aluminummetahydroxide, bentonite, agar-agar, and tragacanth, and mixturesthereof.

For purposes of transdermal (e.g., topical) administration, dilutesterile, aqueous or partially aqueous solutions (usually in about 0.1%to 5% concentration), otherwise similar to the above parenteralsolutions, are prepared.

The pharmaceutical compositions useful in the invention can also beadministered by nasal aerosol or inhalation. Such compositions areprepared according to techniques well-known in the art of pharmaceuticalformulation and can be prepared as solutions in saline, employing benzylalcohol or other suitable preservatives, absorption promoters to enhancebioavailability, fluorocarbons, and/or other conventional solubilizingor dispersing agents.

Compositions for rectal or vaginal administration are preferablysuppositories which can be prepared by mixing the active ingredient or apharmaceutical composition thereof with suitable non-irritatingexcipients or carriers such as cocoa butter, polyethylene glycol or asuppository wax which are solid at room temperature but liquid at bodytemperature and therefore melt in the rectum or vaginal cavity andrelease the drugs.

Other pharmaceutically acceptable carriers include, but are not limitedto, a non-toxic solid, semisolid or liquid filler, diluent,encapsulating material or formulation auxiliary of any type, includingbut not limited to ion exchangers, alumina, aluminum stearate, lecithin,serum proteins, such as human serum albumin, buffer substances such asphosphates, glycine, sorbic acid, potassium sorbate, partial glyceridemixtures of saturated vegetable fatty acids, water, salts orelectrolytes, such as protamine sulfate, disodium hydrogen phosphate,potassium hydrogen phosphate, sodium chloride, zinc salts, colloidalsilica, magnesium trisilicate, polyvinyl pyrrolidone, cellulose-basedsubstances, polyethylene glycol, sodium carboxymethylcellulose,polyacrylates, waxes, polyethylene-polyoxypropylene-block polymers,polyethylene glycol and wool fat.

Solid pharmaceutical excipients include, but are not limited to, starch,cellulose, talc, glucose, lactose, sucrose, gelatin, malt, rice, flour,chalk, silica gel, magnesium stearate, sodium stearate, glycerolmonostearate, sodium chloride, dried skim milk and the like. Liquid andsemisolid excipients can be selected from glycerol, propylene glycol,water, ethanol and various oils, including those of petroleum, animal,vegetable or synthetic origin, e.g., peanut oil, soybean oil, mineraloil, sesame oil, etc. Preferred liquid carriers, particularly forinjectable solutions, include water, saline, aqueous dextrose, andglycols.

Methods of preparing various pharmaceutical compositions with a certainamount of active ingredient are known, or will be apparent in light ofthis disclosure, to those skilled in this art. Other suitablepharmaceutical excipients and their formulations are described inRemington's Pharmaceutical Sciences, edited by E. W. Martin, MackPublishing Company, 19th ed. 1995.

Without further elaboration, it is believed that one skilled in the artcan utilize the present invention to its fullest extent on the basis ofthe preceding description. The following examples are, therefore, to beconstrued as merely illustrative and not a limitation of the scope ofthe present invention in any way.

EXAMPLES Example 1-1 NCTU-SUN-21122:(2-(((4-methoxy-3,5-dimethylpyridin-2-yl)methyl)sulfinyl)-1H-benzo[d]imidazol-5-ylacetate)

To a solution of RS-D7 (0.1 g, 0.30 mmol) in DCM (10 mL) was added NaOH(0.90 mmol) and the reaction mixture was stirred for 5-10 minutes in thenitrogen. Then acetyl chloride (0.60 mmol) was added at 0° C. (in theice bath). After stirring for 5-10 minutes, the reaction was allowed towarm to room temperature and stirred further for 1 hour. The reactionwas extracted with ethyl acetate and pure water. The organic layer wasdried over MgSO₄, filtered and concentrated to give the reactionmixture. The reaction mixture was purified by silica-gel columnchromatography to obtain the pure product.

¹H NMR (400 MHz, Acetone-d₆) δ 8.17 (s, 1H), 7.68 (d, J=8.8 Hz, 1H),7.44 (s, 1H), 7.09 (d, J=8.7 Hz, 1H), 4.71 (s, 2H), 3.75 (s, 3H), 2.29(s, 3H), 2.24 (s, 6H).

LRMS (ESI⁺) m/z: 374.1 (M+H)⁺.

Example 1-2 NCTU-SUN-21124:(2-(((4-methoxy-3,5-dimethylpyridin-2-yl)methyl)sulfinyl)-1H-benzo[d]imidazol-5-ylbenzoate)

Except that acetyl chloride is replaced by benzyl chloride, the otherreactants and preparation steps are similar to those described inExample 1 to afford the title compound.

¹H NMR (400 MHz, Acetone-d₆) δ 8.24 (s, 1H), 8.22 (d, J=1.4 H z, 1H),8.18 (s, 1H), 7.78-7.71 (m, 2H), 7.65-7.59 (m, 3H), 7.27 (dd, J=8.8, 2.2Hz, 1H), 4.74 (s, 2H), 3.76 (s, 3H), 2.26 (s, 3H), 2.25 (s, 3H).

LRMS (ESI⁺) m/z: 436.2 (M+H)⁺.

Example 1-3 NCTU-SUN-26096:(2-(((4-methoxy-3,5-dimethylpyridin-2-yl)methyl)sulfinyl)-1H-benzo[d]imidazol-5-ylbutyrate)

Except that acetyl chloride is replaced by butyryl chloride, the otherreactants and preparation steps are similar to those described inExample 1 to afford the title compound.

¹H NMR (400 MHz, Acetone-d₆) δ 8.17 (s, 1H), 7.68 (d, J=8.7 Hz, 1H),7.43 (d, J=2.0 Hz, 1H), 7.08 (dd, J=8.7, 2.1 Hz, 1H), 4.72 (s, 1H), 3.74(s, 3H), 2.60 (t, J=7.3 Hz, 2H), 2.24 (s, 6H), 1.77 (h, J=7.3 Hz, 3H),1.04 (t, J=7.4 Hz, 3H).

LRMS (ESI⁺) m/z: 402.1 (M+H)⁺.

Example 1-4 NCTU-SUN-26097:(2-(((4-methoxy-3,5-dimethylpyridin-2-yl)methyl)sulfinyl)-1H-benzo[d]imidazol-5-ylcyclohexanecarboxylate)

Except that acetyl chloride is replaced by hexahydrobenzoyl chloride,the other reactants and preparation steps are similar to those describedin Example 1 to afford the title compound.

¹H NMR (400 MHz, Acetone-d₆) δ 8.17 (s, 1H), 7.68 (d, J=8.7 Hz, 1H),7.42 (s, 1H), 7.07 (d, J=8.7 Hz, 1H), 4.72 (s, 2H), 3.75 (s, 3H), 2.64(t, J=11.1 Hz, 1H), 2.24 (s, 7H), 1.88-1.76 (m, 2H), 1.69 (d, J=12.1 Hz,1H), 1.65-1.52 (m, 3H), 1.42 (q, J=11.8 Hz, 2H).

LRMS (ESI⁺) m/z: 442.2 (M+H)⁺.

Example 1-5 NCTU-SUN-26098:(2-(((4-methoxy-3,5-dimethylpyridin-2-yl)methyl)sulfinyl)-1H-benzo[d]imidazol-5-yl4-butylbenzoate)

Except that acetyl chloride is replaced by 4-Butylbenzoyl chloride, theother reactants and preparation steps are similar to those described inExample 1 to afford the title compound.

¹H NMR (400 MHz, Acetone-d₆) δ 8.18 (s, 1H), 8.13 (d, J=8.2 Hz, 2H),7.75 (d, J=8.8 Hz, 1H), 7.61 (s, 1H), 7.45 (d, J=8.2 Hz, 2H), 7.25 (d,J=8.7 Hz, 1H), 4.74 (s, 2H), 3.76 (s, 3H), 2.25 (d, J=6.2 Hz, 6H), 1.66(q, J=7.7 Hz, 3H), 1.47-1.28 (m, 3H), 0.95 (t, J=7.3Hz, 3H).

LRMS (ESI⁺) m/z: 492.1 (M+H)⁺.

Example 1-6 NCTU-SUN-21127:(2-(((4-methoxy-3,5-dimethylpyridin-2-yl)methyl)sulfinyl)-1H-benzo[d]imidazol-5-yl3-methylbenzoate)

Except that acetyl chloride is replaced by m-Toluoyl chloride, the otherreactants and preparation steps are similar to those described inExample 1 to afford the title compound.

¹H NMR (400 MHz, Acetone-d₆) δ 8.18 (s, 1H), 8.06-7.99 (m, 2H), 7.74 (d,J=8.8 Hz, 1H), 7.61 (d, J=2.2 Hz, 1H), 7.56 (d, J=7.5 Hz, 1H), 7.49 (t,J=7.6 Hz, 1H), 7.25 (dd, J=8.7, 2.2 Hz, 1H), 4.76 (d, J=3.2 Hz, 2H),3.74 (s, 3H), 2.47 (s, 3H), 2.25 (s, 3H), 2.23 (s, 3H).

LRMS (ESI⁺) m/z: 450.1 (M+H)⁺.

Example 1-7 NCTU-SUN-27076:2-(((4-methoxy-3,5-dimethylpyridin-2-yl)methyl)sulfinyl)-1H-benzo[d]imidazol-5-ylhexanoate

Except that acetyl chloride is replaced by hexanoyl chloride, the otherreactants and preparation steps are similar to those described inExample 1 to afford the title compound.

¹H NMR (400 MHz, Acetone-d₆) δ 8.17 (s, 1H), 7.68 (d, J=8.7 Hz, 1H),7.44 (s, 1H), 7.09 (d, J=8.8 Hz, 1H), 4.72 (s, 2H), 3.74 (s, 3H), 2.62(t, J=7.4 Hz, 2H), 2.24 (s, 6H), 1.75 (p, J=7.3 Hz, 2H), 1.41 (h, J=7.9,7.5 Hz, 6H), 0.94 (t, J=6.7 Hz, 3H).

LRMS (ESI⁺) m/z: 430.2 (M+H)⁺.

Example 1-8 NCTU-SUN-27077:2-(((4-methoxy-3,5-dimethylpyridin-2-yl)methyl)sulfinyl)-1H-benzo[d]imidazol-5-ylisobutyrate

Except that acetyl chloride is replaced by isobutyryl chloride, theother reactants and preparation steps are similar to those described inExample 1 to afford the title compound.

¹H NMR (400 MHz, Acetone-d₆) δ 8.17 (s, 1H), 7.69 (d, J=8.7 Hz, 1H),7.44 (d, J=2.1 Hz, 1H), 7.08 (dd, J=8.7, 2.1 Hz, 1H), 4.71 (s, 2H), 3.75(s, 3H), 2.89-2.84 (m, 1H), 2.24 (d, J=2.4 Hz, 6H), 1.31 (d, J=7.0 Hz,6H).

LRMS (ESI⁺) m/z: 402.2 (M+H)⁺.

Example 1-9 NCTU-SUN-27078:(2-(((4-methoxy-3,5-dimethylpyridin-2-yl)methyl)sulfinyl)-1H-benzo[d]imidazol-5-ylcyclohex-3-ene-1-carboxylate)

Except that acetyl chloride is replaced by cyclohex-3-enecarbonylchloride, the other reactants and preparation steps are similar to thosedescribed in Example 1 to afford the title compound.

¹H NMR (400 MHz, Acetone-d₆) δ 8.17 (s, 1H), 7.66 (d, J=8.2 Hz, 1H),7.42 (s, 1H), 7.07 (dd, J=8.7, 1.8 Hz, 1H), 5.74 (s, 2H), 4.78 (d,J=13.6 Hz, 1H), 4.73 (d, J=13.7 Hz, 1H), 3.70 (s, 3H), 2.96-2.80 (m,2H), 2.54-2.30 (m, 3H), 2.22 (d, J=2.6 Hz, 6H), 1.95-1.72 (m, 2H).

LRMS (ESI⁺) m/z: 440.1 (M+H)⁺.

Example 1-10 NCTU-SUN-27079:2-(((4-methoxy-3,5-dimethylpyridin-2-yl)methyl)sulfinyl)-1H-benzo[d]imidazol-5-ylcyclohex-3-enecarboxylate

Except that acetyl chloride is replaced by 2-methylbenzoyl chloride, theother reactants and preparation steps are similar to those described inExample 1 to afford the title compound.

¹H NMR (400 MHz, Acetone-d₆) δ 8.20-8.17 (m, 2H), 7.76 (d, J=8.7 Hz,1H), 7.63 (d, J=2.2 Hz, 1H), 7.57 (td, J=7.5, 1.5 Hz, 1H), 7.42 (dt,J=7.4, 3.4 Hz, 2H), 7.27 (dd, J=8.7, 2.2 Hz, 1H), 4.74 (s, 2H), 3.77 (s,3H), 2.67 (s, 3H), 2.26 (s, 4H), 2.25 (s, 4H).

LRMS (ESI⁺) m/z: 450.1 (M+H)⁺.

Example 1-11 NCTU-SUN-28087:(2-(((4-methoxy-3,5-dimethylpyridin-2-yl)methyl)sulfinyl)-1H-benzo[d]imidazol-5-yl4-methylbenzoate)

Except that acetyl chloride is replaced by 4-methylbenzoyl chloride, theother reactants and preparation steps are similar to those described inExample 1 to afford the title compound.

¹H NMR (400 MHz, Acetone-d₆) δ 8.18 (s, 1H), 8.10 (d, J=8.1 Hz, 2H),7.73 (d, J=8.7 Hz, 1H), 7.60 (s, 1H), 7.42 (d, J=7.9 Hz, 2H), 7.24 (d,J=7.1 Hz, 1H), 4.82-4.69 (m, 2H), 3.73 (s, 3H), 2.47 (s, 3H), 2.24 (s,3H), 2.23 (s, 3H).

LRMS (ESI⁺) m/z: 450.1 (M+H)⁺.

Example 1-12 NCTU-SUN-28091:(2-(((4-methoxy-3,5-dimethylpyridin-2-yl)methyl)sulfinyl)-1H-benzo[d]imidazol-5-yl2-nitrobenzoate)

Except that acetyl chloride is replaced by 2-nitrobenzoyl chloride, theother reactants and preparation steps are similar to those described inExample 1 to afford the title compound.

¹H NMR (400 MHz, Acetone-d₆) δ 8.16 (d, J=5.9Hz, 2H), 8.10 (d, J=7.3 Hz,1H), 7.96 (td, J=7.5, 1.8 Hz, 1H), 7.91 (td, J=7.8, 1.8 Hz, 1H), 7.74(dd, J=8.7, 1.5 Hz, 1H), 7.61 (s, 1H), 7.24 (d, J=8.4 Hz, 1H), 4.75 (dd,J=13.7, 5.7 Hz, 2H), 3.69 (s, 3H), 2.20 (s, 6H).

LRMS (ESI⁺) m/z: 481.2 (M+H)⁺.

Example 1-13 NCTU-SUN-28092:(2-(((4-methoxy-3,5-dimethylpyridin-2-yl)methyl)sulfinyl)-1H-benzo[d]imidazol-5-ylcyclopropanecarboxylate)

Except that acetyl chloride is replaced by cyclopropanecarbonylchloride, the other reactants and preparation steps are similar to thosedescribed in Example 1 to afford the title compound.

¹H NMR (400 MHz, Acetone-d₆) δ 8.17 (s, 1H), 7.67 (d, J=8.7 Hz, 1H),7.45 (d, J=2.2 Hz, 1H), 7.09 (dd, J=8.8, 2.2 Hz, 1H), 4.73 (dd, J=13.7,2.5 Hz, 2H), 3.73 (s, 3H), 2.23 (s, 6H), 1.92 (dt, J=12.5, 6.3 Hz, 1H),1.08 (s, 2H), 1.06 (s, 2H).

LRMS (ESI⁺) m/z: 400.2 (M+H)⁺.

Example 1-14 NCTU-SUN-28093:(2-(((4-methoxy-3,5-dimethylpyridin-2-yl)methyl)sulfinyl)-1H-benzo[d]imidazol-5-yl2-ethylbutanoate)

Except that acetyl chloride is replaced by 2-ethylbutanoyl chloride, theother reactants and preparation steps are similar to those described inExample 1 to afford the title compound.

¹H NMR (400 MHz, Acetone-d₆) δ 8.15 (s, 1H), 7.64 (d, J=8.7 Hz, 1H),7.39 (d, J=2.2 Hz, 1H), 7.05 (dd, J=8.8, 2.2 Hz, 1H), 4.81 (dd, J=28.8,13.7 Hz, 2H), 3.65 (s, 3H), 2.51 (tt, J=8.6, 5.5 Hz, 1H), 2.19 (s, 3H),2.18 (s, 3H), 1.74 (m, 4H), 1.04 (t, 7.5Hz, 6H).

LRMS (ESI⁺) m/z: 430.2 (M+H)⁺.

Example 1-15 NCTU-SUN-28094:(2-(((4-methoxy-3,5-dimethylpyridin-2-yl)methyl)sulfinyl)-1H-benzo[d]imidazol-5-yl2-phenylacetate)

Except that acetyl chloride is replaced by 2-phenylacetyl chloride, theother reactants and preparation steps are similar to those described inExample 1 to afford the title compound.

¹H NMR (400 MHz, Acetone-d₆) δ 8.16 (s, 1H), 7.66 (d, J=8.8 Hz, 1H),7.41 (m, 5H), 7.30 (m, 1H), 7.06 (dd, J=8.8, 2.2 Hz, 1H), 4.74 (dd,J=13.7, 19.2 Hz, 2H), 3.98 (s, 2H), 3.70 (s, 3H), 2.21 (s, 6H).

LRMS (ESI⁺) m/z: 450.2 (M+H)⁺.

Example 1-16 NCTU-SUN-28095:(2-(((4-methoxy-3,5-dimethylpyridin-2-yl)methyl)sulfinyl)-1-H-benzo[d]imidazol-5-yl3,5,5-trimethylhexanoate

Except that acetyl chloride is replaced by 3,5,5-trimethylhexanoylchloride, the other reactants and preparation steps are similar to thosedescribed in Example 1 to afford the title compound.

¹H NMR (400 MHz, Acetone-d₆) δ 8.15 (s, 1H), 7.63 (d, J=8.8 Hz, 1H),7.40 (s, 1H), 7.09 (dd, J=8.8, 2.2 Hz, 1H), 4.80 (dd, J=29.0, 13.7 Hz,2H), 3.65 (s, 3H), 2.61 (dd, J=15.0, 6.2 Hz, 1H), 2.44 (dd, J=15.0, 7.9Hz, 1H), 2.19 (m, 1H), 2.19 (s, 3H), 2.18 (s, 3H), 1.43 (dd, J=14.1, 4.0Hz, 1H), 1.23 (dd, J=14.1, 6.5 Hz, 1H), 1.12 (d, J=6.7 Hz, 3H), 0.97 (s,9H).

LRMS (ESI⁺) m/z: 472.1 (M+H)⁺.

Example 1-17 NCTU-SUN-28096:(2-(((5-methoxy-4,6-dimethylpyridin-2-yl)methyl)sulfinyl)-1H-benzo[d]imidazol-5-yl2-ethoxybenzoate)

Except that acetyl chloride is replaced by 2-ethoxybenzoyl chloride, theother reactants and preparation steps are similar to those described inExample 1 to afford the title compound.

¹H NMR (400 MHz, Acetone-d₆) δ 8.18 (s, 1H), 7.92 (dd, J=7.8, 1.8 Hz,1H), 7.71 (d, J=8.8, 1H), 7.58 (m, 2H), 7.22 (dd, J=8.8, 2.3 Hz, 1H),7.18 (d, J=8.5, 1H), 4.80 (dd, J=23.0, 13.7 Hz, 2H), 4.19 (q, J=7.0 Hz,2H), 3.69 (s, 3H), 2.21 (s, 3H), 2.20 (s, 3H), 1.44 (t, J=7.1 Hz, 3H)

LRMS (ESI⁺) m/z: 480.1 (M+H)⁺.

Example 1-18 NCTU-SUN-21123:(2-(((4-methoxy-3,5-dimethylpyridin-2-yl)methyl)sulfinyl)-1H-benzo[d]imidazol-5-ylpropionate)

Except that acetyl chloride is replaced by propionyl chloride, the otherreactants and preparation steps are similar to those described inExample 1 to afford the title compound.

¹H NMR (400 MHz, Acetone-d₆) δ 8.17 (s, 1H), 7.68 (d, J=8.8 Hz, 1H),7.44 (s, 1H), 7.09 (d, J=8.7 Hz, 1H), 4.73 (s, 2H), 3.74 (s, 3H), 2.64(d, J=7.6 Hz, 2H), 2.24 (s, 6H), 1.22 (t, J=7.6 Hz, 3H).

LRMS (ESI⁺) m/z: 388.2 (M+H)⁺.

Example 1-19 NCTU-SUN-21125:(2-(((4-methoxy-3,5-dimethylpyridin-2-yl)methyl)sulfinyl)-1H-benzo[d]imidazol-5-yl4-chlorobenzoate)

Except that acetyl chloride is replaced by 4-chlorobenzoyl chloride, theother reactants and preparation steps are similar to those described inExample 1 to afford the title compound.

¹H NMR (400 MHz, Acetone-d₆) δ 8.33-8.12 (m, 1H), 7.76 (d, J=8.7 Hz,0H), 7.72-7.61 (m, 1H), 7.27 (dd, J=8.7, 2.2 Hz, OH), 4.74 (s, 1H), 3.76(s, 1H), 2.25 (d, J=6.00Hz, 2H).

LRMS (ESI⁺) m/z: 470.2 (M+H)⁺.

Example 1-20 NCTU-SUN-21126:(2-(((4-methoxy-3,5-dimethylpyridin-2-yl)methyl)sulfinyl)-1H-benzo[d]imidazol-5-yl3-nitrobenzoate)

Except that acetyl chloride is replaced by 3-nitrobenzoyl chloride, theother reactants and preparation steps are similar to those described inExample 1 to afford the title compound.

¹H NMR (400 MHz, Acetone-d₆) δ 8.95 (t, J=2.0 Hz, 1H), 8.64-8.56 (m,2H), 8.18 (s, 1H), 7.95 (t, J=8.0 Hz, 1H), 7.77 (d, J=8.8 Hz, 1H), 7.69(d, J=2.2 Hz, 1H), 7.32 (dd, J=8.8, 2.2 Hz, 1H), 4.76 (s, 2H), 3.74 (s,3H), 2.24 (d, J=7.0 Hz, 6H).

LRMS (ESI⁺) m/z: 481.2 (M+H)⁺.

Example 1-21 NCTU-SUN-21128:2-(((4-methoxy-3,5-dimethylpyridin-2-yl)methyl)sulfinyl)-1H-benzo[d]imidazol-5-ylheptanoate

Except that acetyl chloride is replaced by heptanoyl chloride, the otherreactants and preparation steps are similar to those described inExample 1 to afford the title compound.

¹H NMR (400 MHz, Acetone-d₆) δ 8.17 (s, 1H), 7.67 (s, 1H), 7.43 (d,J=2.2 Hz, 1H), 7.08 (dd, J=8.8, 2.1 Hz, 1H), 4.72 (s, 2H), 3.74 (s, 3H),2.62 (s, 2H), 2.24 (s, 6H), 1.81-1.68 (m, 3H), 1.53-1.25 (m, 8H).

LRMS (ESI⁺) m/z: 444.3 (M+H)⁺.

Example 1-22 NCTU-SUN-21129:(2-(((4-methoxy-3,5-dimethylpyridin-2-yl)methyl)sulfinyl)-1H-benzo[d]imidazol-5-yl4-fluorobenzoate)

Except that acetyl chloride is replaced by 4-fluorobenzoyl chloride, theother reactants and preparation steps are similar to those described inExample 1 to afford the title compound.

¹H NMR (400 MHz, Acetone-d₆) δ 8.30 (dd, J=8.6, 5.6 Hz, 1H), 7.75 (d,J=8.7 Hz, 1H), 7.38 (t, J=8.8 Hz, 1H), 7.26 (d, J=8.7 Hz, 1H), 2.24 (d,J=6.5 Hz, 3H).

LRMS (ESI⁺) m/z: 454.1 (M+H)⁺.

Example 1-23 NCTU-SUN-21130:(2-(((4-methoxy-3,5-dimethylpyridin-2-yl)methyl)sulfinyl)-1H-benzo[d]imidazol-5-yl(Z)-2-methylbut-2-enoate)

Except that acetyl chloride is replaced by (Z)-2-methylbut-2-enoylchloride, the other reactants and preparation steps are similar to thosedescribed in Example 1 to afford the title compound.

¹H NMR (400 MHz, Acetone-d₆) δ 8.18 (s, 1H), 7.68 (s, 1H), 7.46 (d,J=2.2 Hz, 1H), 7.19-7.01 (m, 2H), 4.72 (s, 2H), 3.75 (s, 3H), 2.24 (d,J=2.6 Hz, 6H), 1.95 (s, 3H), 1.91 (d, J=7.2 Hz, 3H).

LRMS (ESI⁺) m/z: 414.2 (M+H)⁺.

Example 1-24 NCTU-SUN-21131:(2-(((4-methoxy-3,5-dimethylpyridin-2-yl)methyl)sulfinyl)-1H-benzo[d]imidazol-5-yl2-chloropropanoate)

Except that acetyl chloride is replaced by 2-chloropropanoyl chloride,the other reactants and preparation steps are similar to those describedin Example 1 to afford the title compound.

¹H NMR (400 MHz, Acetone-d₆) δ 8.16 (s, 1H), 7.71 (d, J=8.7 Hz, 1H),7.54-7.40 (m, 1H), 7.13 (dd, J=8.7, 2.0 Hz, 1H), 4.91 (d, J=6.8 Hz, 1H),4.75 (d, J=4.1 Hz, 2H), 3.71 (s, 4H), 2.22 (s, 6H), 1.83 (d, J=6.8 Hz,4H).

LRMS (ESI⁺) m/z: 422.1 (M+H)⁺.

Example 1-25 NCTU-SUN-21132: tert-butyl(2-(((4-methoxy-3,5-dimethylpyridin-2-yl)methyl)sulfinyl)-1H-benzo[d]imidazol-5-yl)carbonate

Except that acetyl chloride is replaced by tert-butyl carbonochloridate,the other reactants and preparation steps are similar to those describedin Example 1 to afford the title compound.

¹H NMR (400 MHz, Acetone-d₆) δ 8.17 (s, 1H), 7.68 (d, J=8.8 Hz, 1H),7.49 (s, 1H), 7.15 (d, J=8.9, 1H), 4.72 (s, 2H), 3.74 (s, 3H), 2.24 (s,6H), 1.54 (s, 9H).

LRMS (ESI⁺) m/z: 432.2 (M+H)⁺.

Example 1-26 NCTU-SUN-12124:(2-(((4-methoxy-3,5-dimethylpyridin-2-yl)methyl)sulfinyl)-1H-benzo[d]imidazol-5-yl(Z)-but-2-enoate)

Except that acetyl chloride is replaced by (Z)-but-2-enoyl chloride, theother reactants and preparation steps are similar to those described inExample 1 to afford the title compound.

¹H NMR (400 MHz, Acetone-d₆) δ 8.18 (s, 1H), 7.69 (d, J=8.4 Hz, 1H),7.47 (dd, J=2.2, 0.4 Hz, 1H), 7.19 (dq, J=15.5, 6.9 Hz, 1H), 7.11 (dd,J=8.8, 2.2 Hz, 1H), 6.13 (dq, J=15.5, 1.7 Hz, 1H), 4.76-4.67 (q, J=13.6,2H), 3.74 (s, 3H), 2.25 (s, 3H), 2.24 (s, 3H), 1.99 (dd, J=6.9, 1.7 Hz,3H).

LRMS (ESI⁺) m/z: 400.2 (M+H)⁺.

Example 1-27 NCTU-SUN-12125:(2-(((4-methoxy-3,5-dimethylpyridin-2-yl)methyl)sulfinyl)-1H-benzo[d]imidazol-5-yl3-methylbut-2-enoate)

Except that acetyl chloride is replaced by 3-methylbut-2-enoyl chloride,the other reactants and preparation steps are similar to those describedin Example 1 to afford the title compound.

¹H NMR (400 MHz, Acetone-d₆) δ 8.18 (s, 1H), 7.69 (d, J=8.7 Hz, 1H),7.45 (d, J=2.0 Hz, 1H), 7.09 (dd, J=8.7, 2.1 Hz, 1H), 5.98 (dt, J=2.6,1.3 Hz, 1H), 4.71 (dd, J=13.6 Hz, 2H), 3.74 (s, 3H), 2.24 (s, 3H), 2.24(s, 3H), 2.22 (d, J=1.2 Hz, 3H), 2.02 (d, J=1.3 Hz, 3H).

LRMS (ESI⁺) m/z: 414.2 (M+H)⁺.

Example 1-28 NCTU-SUN-12122:(2-(((4-methoxy-3,5-dimethylpyridin-2-yl)methyl)sulfinyl)-1H-benzo[d]imidazol-5-ylfuran-2-carboxylate)

Except that acetyl chloride is replaced by furan-2-carbonyl chloride,the other reactants and preparation steps are similar to those describedin Example 1 to afford the title compound.

¹H NMR (400 MHz, Acetone-d₆) δ 8.18 (s, 1H), 7.96 (dd, J=1.8, 0.8 Hz,1H), 7.74 (d, J=8.8 Hz, 1H), 7.60 (d, J=2.1 Hz, 1H), 7.51 (dd, J=3.5,0.8 Hz, 1H), 7.24 (dd, J=8.8, 2.1 Hz, 1H), 6.77 (dd, J=3.5, 1.8 Hz, 1H),4.74 (q, J=13.6 Hz, 2H), 3.75 (s, 3H), 2.25 (s, 3H), 2.24 (s, 3H).

LRMS (ESI⁺) m/z: 426.1 (M+H)⁺.

Example 1-29 NCTU-SUN-12123:(2-(((4-methoxy-3,5-dimethylpyridin-2-yl)methyl)sulfinyl)-1H-benzo[d]imidazol-5-ylacrylate)

Except that acetyl chloride is replaced by acryloyl chloride, the otherreactants and preparation steps are similar to those described inExample 1 to afford the title compound.

¹H NMR (400 MHz, Acetone-d₆) δ 8.17 (s, 1H), 7.71 (d, J=8.8 Hz, 1H),7.51 (d, J=2.2 Hz, 1H), 7.14 (dd, J=8.8, 2.2 Hz, 1H), 6.59 (dd, J=17.3,1.5 Hz, 1H), 6.42 (dd, J=17.3, 10.4 Hz, 1H), 6.11 (dd, J=10.4, 1.5 Hz,1H), 4.73 (q, J=13.6, 2H), 3.74 (s, 3H), 2.24 (s, 3H), 2.24 (s, 3H).

LRMS (ESI⁺) m/z: 386.1 (M+H)⁺.

Example 1-30 NCTU-SUN-12127:(2-(((4-methoxy-3,5-dimethylpyridin-2-yl)methyl)sulfinyl)-1H-benzo[d]imidazol-5-yl2-methylbutanoate)

Except that acetyl chloride is replaced by 2-methylbutanoyl chloride,the other reactants and preparation steps are similar to those describedin Example 1 to afford the title compound.

¹H NMR (400 MHz, Acetone-d₆) δ 8.17 (s, 1H), 7.68 (d, J=8.0 Hz, 1H),7.42 (s, 1H), 7.07 (dd, J=8.7, 1.9 Hz, 1H), 4.80-4.68 (q, J=13.6 Hz,2H), 3.72 (s, 3H), 2.75-2.63 (m, 1H), 2.23 (s, 6H), 1.89-1.77 (m, 1H),1.71-1.60 (m, 1H), 1.29 (d, J=7.0 Hz, 4H), 1.04 (t, J=7.4 Hz, 3H).

LRMS (ESI⁺) m/z: 416.1 (M+H)⁺.

Example 1-31 NCTU-SUN-12128:(2-(((4-methoxy-3,5-dimethylpyridin-2-yl)methyl)sulfinyl)-1H-benzo[d]imidazol-5-yl3-cyclopentylpropanoate)

Except that acetyl chloride is replaced by cyclopentanecarbonylchloride, the other reactants and preparation steps are similar to thosedescribed in Example 1 to afford the title compound.

¹H NMR (400 MHz, Acetone-d₆) δ 8.17 (s, 1H), 7.68 (d, J=8.7 Hz, 1H),7.43 (d, J=2.1 Hz, 1H), 7.08 (dd, J=8.8, 2.2 Hz, 1H), 4.78-4.66 (q,J=13.6, 2H), 3.74 (s, 3H), 2.66-2.61 (m, 2H), 2.24 (s, 6H), 1.94-1.81(m, 3H), 1.77 (dd, J=14.9, 7.4 Hz, 2H), 1.69-1.51 (m, 5H), 1.23-1.13 (m,2H).

LRMS (ESI⁺) m/z: 456.1 (M+H)⁺.

Example 1-32 NCTU-SUN-12129:(2-(((4-methoxy-3,5-dimethylpyridin-2-yl)methyl)sulfinyl)-1H-benzo[d]imidazol-5-yl(E)-3-(2-chlorophenyl)acrylate)

Except that acetyl chloride is replaced by 2-chlorobenzoyl chloride, theother reactants and preparation steps are similar to those described inExample 1 to afford the title compound.

¹H NMR (400 MHz, Acetone-d₆) δ 8.26 (d, J=16.0 Hz, 1H), 8.18 (s, 1H),8.02 (dd, J=7.6, 2.0 Hz, 1H), 7.72 (d, J=7.8 Hz, 1H), 7.58-7.54 (m, 2H),7.48 (m, 2H), 7.20 (dd, J=8.7, 2.0 Hz, 1H), 6.88 (d, J=16.0 Hz, 1H),4.81-4.70 (q, J=13.6, 2H), 3.73 (s, 3H), 2.24 (s, 3H), 2.23 (s, 3H).

LRMS (ESI⁺) m/z: 496.0 (M+H)⁺.

Example 1-33 NCTU-SUN-12130:(2-(((4-methoxy-3,5-dimethylpyridin-2-yl)methyl)sulfinyl)-1H-benzo[d]imidazol-5-yl6-bromohexanoate)

Except that acetyl chloride is replaced by 6-bromohexanoyl chloride, theother reactants and preparation steps are similar to those described inExample 1 to afford the title compound.

¹H NMR (400 MHz, Acetone-d₆) δ 8.17 (s, 1H), 7.68 (d, J=8.5 Hz, 1H),7.44 (d, J=2.3 Hz, 1H), 7.09 (dd, J=8.8, 2.2 Hz, OH), 4.77-4.68 (q,J=13.6, 2H), 3.74 (s, 3H), 3.55 (t, J=6.7 Hz, 2H), 2.66 (t, J=7.4 Hz,2H), 2.35 (s, 6H) 1.99-1.91 (m, 2H), 1.84-1.76 (m, 2H), 1.66-1.56 (m,2H).

LRMS (ESI⁺) m/z: 508.1 (M+H)⁺.

Example 1-34 NCTU-SUN-11021:(2-(((4-methoxy-3,5-dimethylpyridin-2-yl)methyl)sulfinyl)-1H-benzo[d]imidazol-5-yl2-fluorobenzoate)

Except that acetyl chloride is replaced by 2-fluorobenzoyl chloride, theother reactants and preparation steps are similar to those described inExample 1 to afford the title compound.

¹H NMR (400 MHz, Acetone-d₆) δ 8.24-8.13 (m, 2H), 7.78 (dddd, J=8.4,7.4, 4.9, 1.8 Hz, 2H), 7.64 (d, J=2.3 Hz, 1H), 7.48-7.32 (m, 2H), 7.28(dd, J=8.8, 2.2 Hz, 1H), 4.74 (s, 3H), 3.76 (s, 3H), 2.26 (s, 3H), 2.25(s, 3H).

LRMS (ESI⁺) m/z: 454.1 (M+H)⁺.

Example 1-35 NCTU-SUN-11020:(2-(((4-methoxy-3,5-dimethylpyridin-2-yl)methyl)sulfinyl)-1H-benzo[d]imidazol-5-yl4-methoxybenzoate)

Except that acetyl chloride is replaced by 4-methoxybenzoyl chloride,the other reactants and preparation steps are similar to those describedin Example 1 to afford the title compound.

¹H NMR (400 MHz, Acetone-d₆) δ 8.76-7.84 (m, 3H), 7.74 (dd, J=8.8, 0.6Hz, 1H), 7.59 (dd, J=2.2, 0.5 Hz, 1H), 7.23 (dd, J=8.7, 2.2 Hz, 1H),7.13 (d, J=8.9 Hz, 2H), 4.74 (s, 2H), 3.94 (s, 3H), 3.75 (s, 3H), 2.25(s, 3H), 2.24 (s, 3H).

LRMS (ESI⁺) m/z: 466.2 (M+H)⁺.

Example 1-36 NCTU-SUN-11022:(2-(((4-methoxy-3,5-dimethylpyridin-2-yl)methyl)sulfinyl)-1H-benzo[d]imidazol-5-yl(3r,5r,7r)-adamantane-1-carboxylate)

Except that acetyl chloride is replaced by adamantane-1-carbonylchloride, the other reactants and preparation steps are similar to thosedescribed in Example 1 to afford the title compound.

¹H NMR (400 MHz, Acetone-d₆) δ 8.16 (s, 1H), 7.64 (d, J=8.6 Hz, 1H),7.37 (d, J=2.2 Hz, 1H), 7.02 (dd, J=8.8, 2.2 Hz, 1H), 4.83-4.71 (m, 2H),3.69 (s, 3H), 2.22 (s, 3H), 2.21 (s, 3H), 2.20-1.80 (m, 15H)

LRMS (ESI⁺) m/z: 494.2 (M+H)⁺.

Example 1-37 NCTU-SUN-11023:(2-(((4-methoxy-3,5-dimethylpyridin-2-yl)methyl)sulfinyl)-1H-benzo[d]imidazol-5-ylisoxazole-5-carboxylate)

Except that acetyl chloride is replaced by isoxazole-5-carbonylchloride, the other reactants and preparation steps are similar to thosedescribed in Example 1 to afford the title compound.

¹H NMR (400 MHz, Acetone-d₆) δ 8.76 (d, J=1.8 Hz, 1H), 8.17 (s, 1H),7.74 (d, J=8.8 Hz, 1H), 7.67 (d, J=2.2 Hz, 1H), 7.39 (d, J=1.8 Hz, 1H),7.30 (dd, J=8.8, 2.2 Hz, 1H), 4.86-4.72 (m, 2H), 3.70 (s, 3H), 2.22 (s,3H), 2.21 (s, 3H).

LRMS (ESI⁺) m/z: 427.0 (M+H)⁺.

Example 1-38 NCTU-SUN-11030:(2-(((4-methoxy-3,5-dimethylpyridin-2-yl)methyl)sulfinyl)-1H-benzo[d]imidazol-5-yl4-(tert-butyl)benzoate)

Except that acetyl chloride is replaced by 4-(tert-butyl)benzoylchloride, the other reactants and preparation steps are similar to thosedescribed in Example 1 to afford the title compound.

¹H NMR (400 MHz, Methanol-d₄) δ 8.14 (d, J=8.5 Hz, 2H), 8.11 (s, 1H),7.69 (d, J=8.8 Hz, 1H), 7.62 (d, J=8.5 Hz, 2H) 7.51 (d, J=2.2 Hz, 1H),7.21 (dd, J=8.8, 2.2 Hz, 1H), 4.78 (d, J=9.4 Hz, 2H), 3.69 (s, 3H), 2.24(s, 3H), 2.18 (s, 3H), 1.39 (s, 9H).

LRMS (ESI⁺) m/z: 492.1 (M+H)⁺.

Example 1-39 NCTU-SUN-11031:(2-(((4-methoxy-3,5-dimethylpyridin-2-yl)methyl)sulfinyl)-1H-benzo[d]imidazol-5-yl3-chloro-4-fluorobenzoate)

Except that acetyl chloride is replaced by 4-chloro-3-fluorobenzoylchloride, the other reactants and preparation steps are similar to thosedescribed in Example 1 to afford the title compound.

¹H NMR (400 MHz, Acetone-d₆) δ 8.34 (dd, J=7.2, 2.2 Hz, 1H), 8.24 (ddd,J=8.7, 4.7, 2.2 Hz, 1H), 8.18 (t, J=0.8 Hz, 1H), 7.76 (dd, J=8.8, 0.6Hz, 1H), 7.65 (dd, J=2.3, 0.6 Hz, 1H), 7.58 (t, J=8.8 Hz, 1H), 7.28 (dd,J=8.8, 2.2 Hz, 1H), 4.74 (s, 2H), 3.76 (s, 2H), 2.26 (s, 3H), 2.24 (s,3H).

LRMS (ESI⁺) m/z: 488.0 (M+H)⁺.

Example 1-40 NCTU-SUN-25015:(2-(((4-methoxy-3,5-dimethylpyridin-2-yl)methyl)sulfinyl)-1H-benzo[d]imidazol-5-ylpivalate)

Except that acetyl chloride is replaced by pivaloyl chloride, the otherreactants and preparation steps are similar to those described inExample 1 to afford the title compound.

¹H NMR (400 MHz, Acetone-d₆) δ 8.17 (s, 1H), 7.69 (d, J=8.7 Hz, 1H),7.42 (d, J=2.0 Hz, 1H), 7.07 (dd, J=8.7, 2.1 Hz, 1H), 5.62 (s, 1H), 4.71(s, 2H), 3.75 (s, 3H), 2.24 (d, J=2.6 Hz, 6H), 1.37 (s, 9H).

LRMS (ESI⁺) m/z: 416.1 (M+H)⁺.

Example 1-41 NCTU-SUN-25016:(2-(((4-methoxy-3,5-dimethylpyridin-2-yl)methyl)sulfinyl)-1H-benzo[d]imidazol-5-ylpentanoate)

Except that acetyl chloride is replaced by pentanoyl chloride, the otherreactants and preparation steps are similar to those described inExample 1 to afford the title compound.

¹H NMR (400 MHz, Acetone-d₆) δ 8.16 (s, 1H), 7.65 (d, J=8.7 Hz, 1H),7.41 (d, J=2.1 Hz, 1H), 7.07 (dd, J=8.9, 2.1 Hz, 1H), 5.62 (s, 1H),4.96-4.55 (m, 2H), 3.69 (s, 3H), 2.62 (t, J=7.5 Hz, 2H), 2.21 (d, J=3.3Hz, 6H), 1.83-1.64 (m, 2H), 1.46 (q, J=7.4 Hz, 2H), 0.97 (t, J=7.4 Hz,3H).

LRMS (ESI⁺) m/z: 416.1 (M+H)⁺.

Example 1-42 NCTU-SUN-25017:(2-(((4-methoxy-3,5-dimethylpyridin-2-yl)methyl)sulfinyl)-1H-benzo[d]imidazol-5-yl4-nitrobenzoate)

Except that acetyl chloride is replaced by 4-nitrobenzoyl chloride, theother reactants and preparation steps are similar to those described inExample 1 to afford the title compound.

¹H NMR (400 MHz, Acetone-d₆) δ 8.48 (d, J=2.3 Hz, 4H), 8.18 (s, 1H),7.78 (d, J=8.8 Hz, 1H), 7.70 (d, J=2.2 Hz, 1H), 7.33 (dd, J=8.8, 2.3 Hz,1H), 4.74 (s, 2H), 3.76 (s, 3H), 2.25 (d, J=7.2 Hz, 6H).

LRMS (ESI⁺) m/z: 481.2 (M+H)⁺.

Example 1-43 NCTU-SUN-25027:(2-(((4-methoxy-3,5-dimethylpyridin-2-yl)methyl)sulfinyl)-1H-benzo[d]imidazol-5-ylcyclobutanecarboxylate)

Except that acetyl chloride is replaced by cyclobutanecarbonyl chloride,the other reactants and preparation steps are similar to those describedin Example 1 to afford the title compound.

¹H NMR (400 MHz, Acetone-d₆) δ 8.17 (s, 1H), 7.69 (d, J=8.8 Hz, 1H),7.44 (d, J=2.2 Hz, 1H), 7.09 (dd, J=8.8, 2.2 Hz, 1H), 4.71 (s, 2H), 3.75(s, 3H), 3.48 (t, J=8.6 Hz, 1H), 2.39 (dt, J=29.5, 9.1 Hz, 4H), 2.24 (d,J=2.9 Hz, 5H), 2.05 (m, J=2.4 Hz, 2H).

LRMS (ESI⁺) m/z: 414.2 (M+H)⁺.

Example 1-44 NCTU-SUN-25028:(2-(((4-methoxy-3,5-dimethylpyridin-2-yl)methyl)sulfinyl)-1H-benzo[d]imidazol-5-ylthiophene-2-carboxylate)

Except that acetyl chloride is replaced by thiophene-2-carbonylchloride, the other reactants and preparation steps are similar to thosedescribed in Example 1 to afford the title compound.

¹H NMR (400 MHz, Acetone-d₆) δ 8.18 (s, 1H), 8.04 (dd, J=3.8, 1.4 Hz,1H), 7.99 (dd, J=5.0, 1.4 Hz, 1H), 7.74 (d, J=8.8 Hz, 1H), 7.62 (d,J=2.1 Hz, 1H), 7.32 (dd, J=5.1, 3.7 Hz, 1H), 7.25 (dd, J=8.8, 2.2 Hz,1H), 4.75 (d, J=2.1 Hz, 2H), 3.74 (d, J=1.7 Hz, 3H), 2.24 (d, J=5.4 Hz,6H).

LRMS (ESI⁺) m/z: 442.2 (M+H)⁺.

Example 1-45 NCTU-SUN-25029:(2-(((4-methoxy-3,5-dimethylpyridin-2-yl)methyl)sulfinyl)-1H-benzo[d]imidazol-5-yl2-methylbutanoate)

Except that acetyl chloride is replaced by 2-methylbutanoyl chloride,the other reactants and preparation steps are similar to those describedin Example 1 to afford the title compound.

¹H NMR (400 MHz, Acetone-d₆) δ 8.17 (s, 1H), 7.68 (d, J=8.7 Hz, 1H),7.49-7.32 (m, 1H), 7.07 (ddd, J=8.7, 2.3, 1.0 Hz, 1H), 4.76-4.52 (m,2H), 3.74 (d, J=1.0 Hz, 3H), 2.69 (q, J=7.1 Hz, 1H), 2.24 (s, 6H), 1.92—1.75 (m, 1H), 1.65 (dddd, J=13.7, 7.4, 6.3, 1.1 Hz, 1H), 1.29 (dd,J=7.0, 1.0 Hz, 3H), 1.04 (td, J=7.4, 1.0 Hz, 3H).

LRMS (ESI⁺) m/z: 416.1 (M+H)⁺.

Example 1-46 NCTU-SUN-25030:(2-(((4-methoxy-3,5-dimethylpyridin-2-yl)methyl)sulfinyl)-1H-benzo[d]imidazol-5-yl3,3-dimethylbutanoate)

Except that acetyl chloride is replaced by 3,3-dimethylbutanoylchloride, the other reactants and preparation steps are similar to thosedescribed in Example 1 to afford the title compound.

¹H NMR (400 MHz, Acetone-d₆) δ 8.17 (s, 1H), 7.69 (dd, J=8.7, 0.6 Hz,1H), 7.43 (dd, J=2.2, 0.6 Hz, 1H), 7.08 (dd, J=8.7, 2.2 Hz, 1H), 4.72(d, J=1.6 Hz, 2H), 3.74 (s, 3H), 2.50 (s, 2H), 2.24 (d, J=1.3 Hz, 6H),1.15 (s, 9H).

LRMS (ESI⁺) m/z: 430.1 (M+H)⁺.

Example 1-47 NCTU-SUN-25031:(2-(((4-methoxy-3,5-dimethylpyridin-2-yl)methyl)sulfinyl)-1H-benzo[d]imidazol-5-yl2-methoxyacetate)

Except that acetyl chloride is replaced by 2-methoxyacetyl chloride, theother reactants and preparation steps are similar to those described inExample 1 to afford the title compound.

¹H NMR (400 MHz, Acetone-d₆) δ 8.17 (s, 1H), 7.70 (d, J=8.7 Hz, 1H),7.50 (s, 1H), 7.14 (d, J=8.8 Hz, 1H), 4.72 (s, 2H), 4.36 (s, 2H), 3.75(s, 3H), 3.49 (d, J=1.2 Hz, 2H), 2.24 (d, J=2.5 Hz, 6H).

LRMS (ESI⁺) m/z: 404.0 (M+H)⁺.

Example 1-48 NCTU-SUN-25032 (ethyl(2-(((4-methoxy-3,5-dimethylpyridin-2-yl)methyl)sulfinyl)-1H-benzo[d]imidazol-5-yl)carbonate)

Except that acetyl chloride is replaced by ethyl carbonochloridate theother reactants and preparation steps are similar to those described inExample 1 to afford the title compound.

¹H NMR (400 MHz, Acetone-d₆) δ 8.17 (s, 1H), 7.69 (d, J=8.8 Hz, 1H),7.53 (d, J=2.2 Hz, 1H), 7.18 (dd, J=8.8, 2.2 Hz, 1H), 4.74 (d, J=2.6 Hz,2H), 4.30 (q, J=7.1 Hz, 2H), 3.73 (s, 3H), 2.23 (s, 7H), 1.35 (t, J=7.1Hz, 4H).

LRMS (ESI⁺) m/z: 404.0 (M+H)⁺.

Example 2-1 26065: Methyl1-(furan-2-ylmethyl)-2-(((4-methoxy-3,5-dimethylpyridin-2-yl)methyl)amino)-1H-benzo[d]imidazole-5-carboxylate

To a solution of 4-fluoro-3-nitrobenzoic acid 1 (5.0 g, 27.0 mmol) indry MeOH (30 mL), H₂SO₄ (5 mL, 0.3 M) was added and the reaction mixturewas heated to reflux for 12 h. The solvent was removed under reducedpressure, crude reaction mixture was dissolved in EtOAc (150 mL), washedwith saturated NaHCO₃ (20 mL×2), water (10 mL×2) and brine (10 mL). TheEtOAc layer was dried over anhydrous MgSO₄ and evaporated to get methyl4-fluoro-3-nitrobenzoate 2 (95%) as a white solid.

Compound 2 (2.0 g, 10.2 mmol) and 2-Aminomethylfuran (3 equiv.) in dryCH₂Cl₂ (50 mL) were stirred at room temperature for 2 h. Upon completionof reaction the solvent was removed and the crude product was purifiedby flash column chromatography to afford nitro benzoates 3 (90%).

To a solution of compound 3 (2.0 g, 4.8 mmol) in dry MeOH (100 mL), zincdust (15 equiv., 71.4 mmol) and ammonium formate (7.5 equiv., 35.7 mmol)were added and the resulting reaction mixture was stirred at roomtemperature for 30 min. Upon completion of reaction, Zn dust wasfiltered through a bed of celite, filtrate was evaporated and theproduct was dissolved in CH₂Cl₂ (100 mL). The precipitated ammoniumformate was filtered off and the solvent was evaporated to furnishcompound 4 (92%).

Use DCM to dissolve compound 4 (1.0 g, 4.0 mmol) then add 1.2 equiv.CNBr to react at room temperature. After 8 hours the mixture can beextracted with DCM and water. The solvent was removed and the crudeproduct was purified by flash column chromatography to afford 5 (60%)

To a solution of methyl2-amino-1-(furan-2-ylmethyl)-1H-benzo[d]imidazole-5-carboxylate 5 (0.05g, 0.18 mmol) in acetoniritle (10 mL) was added K₂CO₃ (0.0497 g, 0.36mmol) and KI (0.0089 g, 0.054 mmol) followed by2-(chloromethyl)-4-methoxy-3,5-dimethylpyridine 6 (0.041 g, 0.22 mmol)and the reaction mixture was allowed to reflux for six hours. After 6 h,the solvent was evaporated and the reaction mixture was diluted withsaturated aq. NaHCO₃ (10 mL) and extracted with EtOAc (3*10 mL).

The combined organic phase was washed with saturated brine (30 mL). Thecrude product was purified by silica-gel column chromatography using 8%methanol/EtOAc to obtain the pure product NCTU-SUN-26065 as a whitesolid 0.053 g (71%).

¹H NMR (400 MHz, Chloroform-d) δ 8.34 (s, 1H), 7.83 (dd, J=8.3, 1.4 Hz,1H), 7.73 (d, J=1.2 Hz, 1H), 7.34 (dd, J=1.8, 0.7 Hz, 1H), 7.13 (d,J=8.3 Hz, 1H), 6.37 (d, J=3.3 Hz, 1H), 6.32 (dd, J=3.2, 1.9 Hz, 1H),5.42 (s, 2H), 5.10 (s, 2H), 3.89 (s, 3H), 3.87 (s, 3H), 2.33 (s, 3H),2.30 (s, 3H); ¹³C NMR (101 MHz, Chloroform-d) δ 166.75, 153.88, 142.73,133.38, 128.36, 124.86, 124.00, 110.60, 109.61, 109.04, 108.26, 77.22,61.46, 52.24, 38.50, 31.90, 29.67, 29.33, 22.66, 14.64, 14.09, 11.39;LRMS (ESI+): m/z 422.3 (M+H)⁺.

Example 2-2 21098: Methyl2-(((4-methoxy-3,5-dimethylpyridin-2-yl)methyl)amino)-1-propyl-1H-benzo[d]imidazole-5-carboxylate

Except that amine is replaced by propan-1-amine, the other reactants andpreparation steps are similar to those described in Example 2-1 toafford the title compound.

¹H NMR (400 MHz, Methanol-d₄) δ 7.96 (s, 1H), 7.91 (d, J=8.4 Hz, 1H),7.68 (s, 1H), 7.42 (d, J=8.4 Hz, 1H), 5.41 (s, 2H), 4.09 (t, J=7.4 Hz,2H), 3.81 (d, J=13.8 Hz, 6H), 2.34 (s, 3H), 2.20 (s, 3H), 1.85 (d, J=7.9Hz, 2H), 1.02 (t, J=7.4 Hz, 3H); ¹³C NMR (101 MHz, Methanol-d₄) δ164.54, 148.32, 134.44, 126.25, 124.69, 124.43, 109.95, 108.43, 59.29,51.27, 45.10, 43.91, 29.31, 20.86, 11.90, 9.78, 9.16 ; LRMS (ESI+): m/z383.3 (M+H)⁺.

Example 2-3 21103: Methyl2-(((4-methoxy-3,5-dimethylpyridin-2-yl)methyl)amino)-1-(3-methoxypropyl)-1H-benzo[d]imidazole-5-carboxylate

Except that amine is replaced by 3-methoxypropan-1-amine, the otherreactants and preparation steps are similar to those described inExample 2-1 to afford the title compound.

¹H NMR (400 MHz, Methanol-d₄) δ 8.10 (s, 1H), 7.90 (t, J=1.8 Hz, 1H),7.67 (dt, J=8.4, 1.9 Hz, 1H), 7.11 (dd, J=8.4, 2.1 Hz, 1H), 4.58 (d,J=2.1 Hz, 2H), 4.09-4.01(m, 2H), 3.82 (d, J=2.1 Hz, 3H), 3.73 (d, J=2.1Hz, 3H), 3.19 (d, J=2.1 Hz, 3H), 2.19 (dd, J=10.1, 2.1 Hz, 6H), 1.96 (p,J=6.2 Hz, 2H); ¹³C NMR (101 MHz, Methanol-d₄) δ 167.93, 164.20, 155.50,153.88, 147.84, 141.23, 138.15, 125.49, 124.19, 122.68, 121.59, 116.14,106.85, 68.04, 59.16, 57.48, 50.95, 45.26, 38.49, 28.17, 11.97, 9.08 ;LRMS (ESI+): m/z 413.3 (M+H)⁺.

Example 2-4 26070:1-(furan-2-ylmethyl)-2-(((4-methoxy-3,5-dimethylpyridin-2-yl)methyl)amino)-1H-benzo[d]imidazole-5-carboxylicacid

To a solution of 4-fluoro-3-nitrobenzoic acid 1 (5.0 g, 27.0 mmol) indry MeOH (30 mL), H₂SO₄ (5 mL, 0.3 M) was added and the reaction mixturewas heated to reflux for 12 h. The solvent was removed under reducedpressure, crude reaction mixture was dissolved in EtOAc (150 mL), washedwith saturated NaHCO₃ (20 mL×2), water (10 mL×2) and brine (10 mL). TheEtOAc layer was dried over anhydrous MgSO₄ and evaporated to get methyl4-fluoro-3-nitrobenzoate 2 (95%) as a white solid.

Compound 2 (2.0 g, 10.2 mmol) and furan-2-ylmethanamine (3 equiv.) indry CH₂Cl₂ (50 mL) were stirred at room temperature for 2 h. Uponcompletion of reaction the solvent was removed and the crude product waspurified by flash column chromatography to afford nitro benzoates 3(90%).

To a solution of compound 3 (2.0 g, 4.8 mmol) in dry MeOH (100 mL), zincdust (15 equiv., 71.4 mmol) and ammonium formate (7.5 equiv., 35.7 mmol)were added and the resulting reaction mixture was stirred at roomtemperature for 30 min. Upon completion of reaction, Zn dust wasfiltered through a bed of celite, filtrate was evaporated and theproduct was dissolved in CH₂Cl₂ (100 mL). The precipitated ammoniumformate was filtered off and the solvent was evaporated to furnishcompound 4 (92%).

Use DCM to dissolve compound 4 (1.0 g, 4.0 mmol) then add 1.2 equiv.CNBr to react at room temperature. After 8 hours the mixture can beextracted with DCM and water. The solvent was removed and the crudeproduct was purified by flash column chromatography to afford 5 (60%)

To a solution of methyl2-amino-1-(furan-2-ylmethyl)-1H-benzo[d]imidazole-5-carboxylate 5 (0.05g, 0.18 mmol) in acetoniritle (10 mL) was added K₂CO₃ (0.0497 g, 0.36mmol) and KI (0.0089 g, 0.054 mmol) followed by2-(chloromethyl)-4-methoxy-3,5-dimethylpyridine 6 (0.041 g, 0.22 mmol)and the reaction mixture was allowed to reflux for six hours. After 6 h,the solvent was evaporated and the reaction mixture was diluted withsaturated aq. NaHCO₃ (10 mL) and extracted with EtOAc (3*10 mL). Thecombined organic phase was washed with saturated brine (30 mL). Thecrude product was purified by silica-gel column chromatography using 8%methanol/EtOAc to obtain Methyl1-(furan-2-ylmethyl)-2-(((4-methoxy-3,5-dimethylpyridin-2-yl)methyl)amino)-1H-benzo[d]imidazole-5-carboxylate7.

And add NaOH (0.0251 g, 0.63 mmol) to a solution of Methyl1-(furan-2-ylmethyl)-2-(((4-methoxy-3,5-dimethylpyridin-2-yl)methyl)amino)-1H-benzo[d]imidazole-5-carboxylate7 (0.053 g, 0.126 mmol) in the EtOH/H₂O (1/1, 3mL) in the refluxcondition. After 1 h, the solvent was evaporated and the reactionmixture was diluted with saturated aq. HCl (10 mL) and extracted withEtOAc (3*10 mL). The combined organic phase was washed with saturatedbrine (10 mL). The crude product was purified by silica-gel columnchromatography using 20% methanol/EtOAc to obtain the pure product as awhite solid 0.030 g (65%).

LRMS (ESI+): m/z 407.2 (M+H)⁺.

Example 2-5 26066: Methyl2-(((4-methoxy-3,5-dimethylpyridin-2-yl)methyl)amino)-1-pentyl-1H-benzo[d]imidazole-5-carboxylate

Except that amine is replaced by pentan-1-amine, the other reactants andpreparation steps are similar to those described in Example 2-1 toafford the title compound.

¹H NMR (400 MHz, Chloroform-d) δ 8.08 (s, 1H), 8.01 (dd, J=8.4, 1.2 Hz,1H), 7.72 (s, 1H), 7.29 (d, J=8.5 Hz, 1H), 5.92 (s, 2H), 4.49 (t, J=7.2Hz, 2H), 3.89 (s, 6H), 2.47 (s, 3H), 2.26 (s, 3H), 1.96-1.83 (m, 2H),1.54-1.41 (m, 2H), 1.44-1.29 (m, 2H), 0.88 (t, J=7.2 Hz, 3H); LRMS(ESI+): m/z 411.2 (M+H)⁺.

Example 2-6 21102:2-(((4-methoxy-3,5-dimethylpyridin-2-yl)methyl)amino)-1-propyl-1H-benzo[d]imidazole-5-carboxylicacid

Except that amine is replaced by propan-1-amine, the other reactants andpreparation steps are similar to those described in Example 2-4 toafford the title compound.

¹H NMR (400 MHz, Methanol-d₄) δ 8.04 (d, J=8.3 Hz, 1H), 7.95 (s, 1H),7.89 (s, 1H), 7.64 (d, J=8.1 Hz, 1H), 5.57 (s, 2H), 4.25 (t, J=7.3 Hz,2H), 3.83 (s, 3H), 2.41 (s, 3H), 2.21 (s, 3H), 1.92 (d, J=7.3 Hz, 2H),1.07 (t, J=7.3 Hz, 3H); ¹³C NMR (101 MHz, Methanol-d₄) δ 150.03, 148.40,130.63, 126.40, 125.74, 111.55, 109.87, 59.38, 45.34, 44.56, 20.95,11.93, 9.68, 9.17; LRMS (ESI+): m/z 369.2 (M+H)⁺.

Example 2-7 26071: Methyl2-(((4-methoxy-3,5-dimethylpyridin-2-yl)methyl)amino)-1-(4-methoxybenzyl)-1H-benzo[d]imidazole-5-carboxylate

Except that amine is replaced by (4-methoxyphenyl)methanamine, the otherreactants and preparation steps are similar to those described inExample 2-1 to afford the title compound.

¹H NMR (400 MHz, Methanol-d₄) δ 8.02 (s, 1H), 7.83 (dd, J=8.4, 1.5 Hz,1H), 7.68 (d, J=1.6 Hz, 1H), 7.29 (d, J=8.7 Hz, 2H), 7.23 (d, J=8.4 Hz,1H), 6.92 (d, J=8.7 Hz, 2H), 5.43 (s, 2H), 5.29 (s, 2H), 3.83 (s, 3H),3.81 (s, 3H), 3.77 (s, 3H), 2.36 (s, 3H), 2.24 (s, 3H); LRMS (ESI+): m/z461.2 (M+H)⁺.

Example 2-8 21105:2-(bis((4-methoxy-3,5-dimethylpyridin-2-yl)methyl)amino)-1-(2-(cyclohex-1-en-1-yl)ethyl)-1H-benzo[d]imidazole-5-carboxylicacid

Except that amine is replaced by 2-(cyclohex-1-en-1-yl)ethanamine, theother reactants and preparation steps are similar to those described inExample 2-4 to afford the title compound.

¹H NMR (400 MHz, Methanol-d₄) δ 8.17 (s, 2H), 8.07 (s, 1H), 7.82 (d,J=8.2 Hz, 1H), 7.26 (d, J=8.3 Hz, 1H), 5.13 (s, 1H), 4.77 (s, 4H), 4.11(t, J=7.8 Hz, 2H), 3.80-3.69 (m, 6H), 2.29 (t, J=8.4 Hz, 2H), 2.18 (d,J=21.8 Hz, 12H), 1.76 (s, 4H), 1.49-1.36 (m, 4H); ¹³C NMR (101 MHz,Methanol-d₄) δ 156.95, 145.93, 139.17, 131.88, 130.28, 125.53, 118.06,117.75, 117.05, 115.18, 114.79, 110.01, 100.70, 51.25, 46.58, 35.22,28.52, 19.80, 16.65, 14.33, 13.64, 3.99, 1.48; LRMS (ESI+): m/z 584.3(M+H)+.

Example 2-9 21104:2-(bis((4-methoxy-3,5-dimethylpyridin-2-yl)methyl)amino)-1-(3-methoxypropyl)-1H-benzo[d]imidazole-5-carboxylicacid

Except that amine is replaced by 3-methoxypropan-1-amine, the otherreactants and preparation steps are similar to those described inExample 2-4 to afford the title compound.

¹H NMR (400 MHz, DMSO-d₆) δ 8.06 (s, 2H), 7.88 (d, J=1.6 Hz, 1H), 7.68(dd, J=8.4, 1.6 Hz, 1H), 7.32 (d, J=8.4 Hz, 1H), 4.65 (s, 4H), 4.17 (t,J=7.6 Hz, 2H), 3.62 (s, 6H), 3.20 (t, J=5.9 Hz, 2H), 3.09 (s, 3H), 2.10(s, 6H), 2.05 (s, 6H), 1.94-1.88 (m, 2H); ¹³C NMR (101 MHz, DMSO-d₆) δ168.52, 163.68, 158.90, 155.26, 148.49, 141.33, 125.19, 125.04, 124.05,122.18, 118.11, 109.15, 69.30, 60.07, 58.30, 54.87, 41.74, 29.10, 13.24,10.68; LRMS (ESI+): m/z 548.3 (M+H)⁺.

Example 2-10 26076:2-(((4-methoxy-3,5-dimethylpyridin-2-yl)methyl)amino)-1-pentyl-1H-benzo[d]imidazole-5-carboxylicacid

Except that amine is replaced by pentan-1-amine, the other reactants andpreparation steps are similar to those described in Example 2-4 toafford the title compound.

¹H NMR (400 MHz, DMSO-d₆) δ 7.88 (s, 1H), 7.81 (dd, J=8.2, 1.3 Hz, 1H),7.70 (d, J=1.6 Hz, 1H), 7.39 (d, J=8.4 Hz, 2H), 5.59 (s, 2H), 4.23 (t,J=6.9 Hz, 2H), 3.72 (s, 3H), 2.30 (s, 3H), 2.11 (s, 3H), 1.83 (s, 2H),1.30 (dq, J=6.7, 3.3 Hz, 4H), 0.90-0.73 (m, 3H) ; LRMS (ESI+): m/z 397.2(M+H)⁺.

Example 2-11 26077:2-(((4-methoxy-3,5-dimethylpyridin-2-yl)methyl)amino)-1-(4-methoxybenzyl)-1H-benzo[d]imidazole-5-carboxylicacid

Except that amine is replaced by (4-methoxyphenyl)methanamine, the otherreactants and preparation steps are similar to those described inExample 2-4 to afford the title compound.

LRMS (ESI+): m/z 447.2 (M+H)⁺.

Example 2-12 21115:2-(((4-methoxy-3,5-dimethylpyridin-2-yl)methyl)amino)-1-(3-methoxypropyl)-1H-benzo[d]imidazole-5-carboxylicacid

Except that amine is replaced by 3-methoxypropan-1-amine, the otherreactants and preparation steps are similar to those described inExample 2-4 to afford the title compound.

¹H NMR (400 MHz, Methanol-d₄) δ 8.20 (s, 1H), 7.98-7.92 (m, 2H), 7.50(d, J=8.7 Hz, 1H), 4.86 (s, 2H), 4.34 (t, J=6.7 Hz, 2H), 3.87 (s, 3H),3.44 (t, J=5.6 Hz, 2H), 3.27 (s, 3H), 2.35 (s, 3H), 2.28 (s, 3H),2.17-2.10 (m, 2H); ¹³C NMR (101 MHz, Methanol-d₄) δ 169.05, 152.95,147.73, 136.45, 132.73, 127.94, 127.04, 126.46, 125.88, 114.80, 110.19,69.41, 60.81, 58.69, 46.10, 41.07, 28.74, 13.36, 10.48 ; LRMS (ESI+):m/z 399.2 (M+H)⁺.

Example 2-13 21116: Methyl1-(2-(cyclohex-1-en-1-yl)ethyl)-2-(((4-methoxy-3,5-dimethylpyridin-2-yl)methyl)amino)-1H-benzo[d]imidazole-5-carboxylate

Except that amine is replaced by 2-(cyclohex-1-en-1-yl)ethanamine, theother reactants and preparation steps are similar to those described inExample 2-1 to afford the title compound.

¹H NMR (400 MHz, Acetone-d₆) δ 8.20 (s, 1H), 7.94 (d, J=1.4 Hz, 1H),7.70 (dt, J=8.2, 1.4 Hz, 1H), 7.22 (dd, J=8.3, 1.2 Hz, 1H), 6.71 (s,1H), 5.33 (dt, J=4.8, 2.3 Hz, 1H), 4.68 (d, J=3.7 Hz, 2H), 4.17 (td,J=7.2, 1.2 Hz, 2H), 3.84 (d, J=1.2 Hz, 3H), 3.79 (d, J=1.2 Hz, 3H), 2.41(t, J=7.2 Hz, 2H), 2.28 (s, 3H), 2.23 (s, 3H), 2.04 (h, J=1.8 Hz, 2H),2.02-1.97 (m, 2H), 1.82-1.76 (m, 2H), 1.51 (t, J=5.9 Hz, 2H), 1.42-1.37(m, 2H); ¹³C NMR (101 MHz, Acetone-d₆) δ 167.29, 163.89, 155.45, 154.37,148.06, 142.70, 138.71, 133.89, 125.06, 124.16, 123.65, 122.50, 120.86,116.95, 107.03, 59.48, 50.95, 45.16, 41.27, 36.41, 29.18, 8.99, 28.79,28.11, 24.91, 22.61, 21.81, 12.36, 9.35.

Example 2-14 21117:1-(2-(cyclohex-1-en-1-yl)ethyl)-2-(((4-methoxy-3,5-dimethylpyridin-2-yl)methyl)amino)-1H-benzo[d]imidazole-5-carboxylicacid

Except that amine is replaced by 2-(cyclohex-1-en-1-yl)ethanamine, theother reactants and preparation steps are similar to those described inExample 2-4 to afford the title compound.

¹H NMR (400 MHz, DMSO-d₆) δ 8.15 (s, 1H), 7.70 (s, 1H), 7.56 (d, J=8.2Hz, 1H), 7.15 (d, J=8.3 Hz, 1H), 7.08 (t, J=5.3 Hz, 1H), 5.23 (s, 1H),4.61 (d, J=4.2 Hz, 2H), 4.12 (t, J=7.1 Hz, 2H), 3.69 (s, 3H), 2.28-2.13(m, 8H), 1.90 (s, 2H), 1.72 (s, 2H), 1.38 (dq, J=31.9, 5.4 Hz, 4H); ¹³CNMR (101 MHz, DMSO-d₆) δ 168.24, 155.18, 155.12, 147.74, 141.57, 137.88,133.55, 124.39, 123.56, 123.09, 123.01, 120.32, 115.84, 106.77, 59.43,45.42, 40.30, 35.64, 27.52, 24.33, 21.97, 21.29, 12.55, 9.85.

Example 2-15 21118: Methyl2-(((4-methoxy-3,5-dimethylpyridin-2-yl)methyl)amino)-1-phenethyl-1H-benzo[d]imidazole-5-carboxylate

Except that amine is replaced by 2-phenylethanamine, the other reactantsand preparation steps are similar to those described in Example 2-1 toafford the title compound.

¹H NMR (400 MHz, Methanol-d₄) δ 8.16 (s, 1H), 7.89 (s, 1H), 7.63 (d,J=8.2 Hz, 1H), 7.10 (dt, J=16.2, 7.1 Hz, 5H), 6.99 (d, J=8.2 Hz, 1H),4.57 (s, 3H), 4.30 (t, J=7.0 Hz, 2H), 3.82 (d, J=25.8 Hz, 6H), 3.05 (t,J=7.0 Hz, 2H), 2.29-2.20 (m, 6H); ¹³C NMR (101 MHz, Methanol-d₄) δ169.48, 165.74, 156.92, 155.57, 149.24, 142.52, 139.50, 139.30, 130.05,129.59, 127.73, 127.01, 125.84, 123.98, 122.90, 117.45, 108.52, 60.62,52.38, 49.85, 46.69, 44.97, 40.00, 39.79, 39.58, 39.37, 39.16, 35.62,13.36, 10.56 ; LRMS (ESI+): m/z 445.4 (M+H)⁺.

Example 2-16 21119:2-(((4-methoxy-3,5-dimethylpyridin-2-yl)methyl)amino)-1-phenethyl-1H-benzo[d]imidazole-5-carboxylicacid

Except that amine is replaced by 2-phenylethanamine, the other reactantsand preparation steps are similar to those described in Example 2-4 toafford the title compound.

¹H NMR (400 MHz, Methanol-d₄) δ 8.19 (s, 1H), 7.89 (d, J=1.5 Hz, 1H),7.79 (dd, J=8.5, 1.7 Hz, 1H), 7.19-7.07 (m, 6H), 4.73 (s, 2H), 4.48 (t,J=6.8 Hz, 2H), 3.87 (s, 3H), 3.16 (t, J=6.8 Hz, 2H), 2.29 (d, J=14.6 Hz,6H); ¹³C NMR (101 MHz, Methanol-d₄) δ 169.15, 167.25, 153.40, 153.06,148.02, 138.56, 136.34, 130.16, 129.70, 128.21, 128.04, 127.16, 126.66,126.02, 114.72, 110.61, 61.03, 46.15, 45.80, 34.84, 13.58, 10.68.

Example 2-17 21120:2-(bis((4-methoxy-3,5-dimethylpyridin-2-yl)methyl)amino)-1-propyl-1H-benzo[d]imidazole-5-carboxylicacid

Except that amine is replaced by propan-1-amine, the other reactants andpreparation steps are similar to those described in Example 2-4 toafford the title compound.

¹H NMR (400 MHz, DMSO-d₆) δ 8.09 (s, 2H), 7.88 (d, J=1.6 Hz, 1H), 7.68(dd, J=8.3, 1.6 Hz, 1H), 7.39 (d, J=8.4 Hz, 1H), 4.63 (s, 4H), 4.11 (t,J=7.9 Hz, 2H), 3.62 (s, 6H), 2.08 (d, J=17.4 Hz, 12H), 1.66 (d, J=7.7Hz, 2H), 0.73 (t, J=7.3 Hz, 3H).

Example 2-18 21121:2-(bis((4-methoxy-3,5-dimethylpyridin-2-yl)methyl)amino)-1-phenethyl-1H-benzo[d]imidazole-5-carboxylicacid

Except that amine is replaced by 2-phenylethanamine, the other reactantsand preparation steps are similar to those described in Example 2-4 toafford the title compound.

¹H NMR (400 MHz, DMSO-d₆) δ 8.07 (s, 2H), 7.89 (d, J=1.5 Hz, 1H), 7.67(dd, J=8.4, 1.7 Hz, 1H), 7.40 (d, J=8.4 Hz, 1H), 7.19-7.13 (m, 3H),7.10-7.05 (m, 2H), 4.64 (s, 4H), 4.39 (t, J=8.0 Hz, 2H), 3.59 (s, 6H),2.97 (t, J=8.1 Hz, 2H), 2.07 (d, J=11.5 Hz, 12H); ¹³C NMR (101 MHz,DMSO-d₆) δ 168.15, 163.34, 154.81, 148.03, 140.97, 138.79, 138.04,128.79, 128.39, 126.52, 124.88, 124.76, 123.79, 122.04, 117.97, 109.35,59.74, 55.15, 45.31, 34.51, 12.91, 10.42.

Example 3-1 NCTU-SUN-26079 : Methyl3-(furan-2-ylmethyl)-2-(((4-methoxy-3,5-dimethylpyridin-2-yl)methyl)amino)-3,4-dihydroquinazoline-7-carboxylate

To a solution of 4-(bromomethyl)-3-nitrobenzoic acid 1 (5.0 g, 27.0mmol) in dry MeOH/CH₂Cl₂ (3 mL: 30 mL), was added DCC (1.2 equiv) andDMAP (0.005 equiv) and the reaction mixture was stirred at roomtemperature for 16 hours. The byproduct DCU was filtered off and crudewas purified by flash column chromatography to get methyl4-(bromomethyl)-3-nitrobenzoate 2 (76%) as an off-white solid.

Compound 2 (4.0 g, 14.5 mmol) and 2-aminomethylfuran (3 equiv) in dryCH₂Cl₂ (50 mL) were stirred at room temperature for 48 hours. Uponcompletion of reaction the solvent was removed and the crude product waspurified by flash column chromatography to afford nitro benzoate 3(82%).

To a solution of compound 3 (3.65 g, 11.9 mmol) in dry MeOH (100 mL),SnCl₂.2H₂O (3.5 equiv) was added and the resulting reaction mixture wasrefluxed for 10 minutes. Upon completion of reaction, the byproduct wasfiltered through a bed of celite and filtrate was evaporated. The crudeproduct was portioned between 1 N NaOH and ethyl acetate. The aqueouslayer was extracted with ethyl acetate (3×20 mL) and the combined layerswere dried over MgSO₄ and concentrated under reduced pressure to furnishcompound 4 (87%).

Use DCM to dissolve compound 4 (1.0 g, 3.8 mmol) then add 1.2 equiv.CNBr to react at room temperature. After 8 hours the mixture can beextracted with DCM and water. The solvent was removed and the crudeproduct was purified by flash column chromatography to afford 5 (60%).

To a solution of methyl2-amino-3-(furan-2-ylmethyl)-3,4-dihydroquinazoline-7-carboxylate 5 (0.3g, 1.05 mmol) in acetoniritle (20 mL) was added K₂CO₃ (0.29 g, 2.1 mmol)and KI (0.005 g, 0.03 mmol) followed by2-(chloromethyl)-4-methoxy-3,5-dimethylpyridine 6 (0.722 g, 3.89 mmol)and the reaction mixture was allowed to reflux for six hours. After 24hours, the solvent was evaporated and the reaction mixture was dilutedwith saturated aq. NaHCO₃ (30 mL) and extracted with EtOAc (3*30 mL).

The combined organic phase was washed with saturated brine (30 mL). Thecrude product was purified by silica-gel column chromatography using 8%methanol/EtOAc to obtain the pure product NCTU-SUN-26079 as a whitesolid 0.43 g (70%).

¹H NMR (400 MHz, Methanol-d₄) δ 8.16 (s, 1H), 7.81 (dd, J=7.9, 1.4 Hz,1H), 7.56 (dd, J=1.8, 0.8 Hz, 1H), 7.37 (d, J=1.4 Hz, 1H), 7.32 (d,J=7.9 Hz, 1H), 6.60 (d, J=3.3 Hz, 1H), 6.47 (dd, J=3.3, 1.9 Hz, 1H),5.28 (s, 2H), 4.88 (s, 2H), 4.61 (s, 2H), 3.88 (s, 3H), 3.83 (s, 3H),2.45 (s, 3H), 2.28 (s, 3H) ; LRMS (ESI+): m/z 435.3 (M+H)⁺.

Example 3-2 21106: Methyl3-(2-(cyclohex-1-en-1-yl)ethyl)-2-(((4-methoxy-3,5-dimethylpyridin-2-yl)methyl)amino)-3,4-dihydroquinazoline-7-carboxylate

Except that amine is replaced by 2-(cyclohex-1-en-1-yl)ethanamine, theother reactants and preparation steps are similar to those described inExample 3-1 to afford the title compound.

¹H NMR (400 MHz, Methanol-d₄) δ 8.17 (s, 1H), 7.83 (dd, J=7.9, 1.5 Hz,1H), 7.40-7.33 (m, 2H), 5.24 (s, 2H), 5.16 (s, 1H), 4.61 (s, 2H), 3.88(s, 3H), 3.84 (s, 3H), 3.76 (s, 2H), 2.46 (s, 3H), 2.28 (s, 3H), 2.12(d, J=8.1 Hz, 2H), 1.99 (s, 2H), 1.63-1.55 (m, 4H), 1.43-1.36 (m, 2H);LRMS (ESI+): m/z 314.2 (M+H)⁺.

Example 3-3 26072: Methyl2-(bis((4-methoxy-3,5-dimethylpyridin-2-yl)methyl)amino)-3-(furan-2-ylmethyl)-3,4-dihydroquinazoline-7-carboxylate

Same as described in Example 3-1 to afford the title compound.

¹H NMR (400 MHz, Methanol-d₄) δ 8.21-8.19 (m, 1H), 8.07 (d, J=0.8 Hz,1H), 7.83 (dd, J=7.9, 1.5 Hz, 1H), 7.57 (d, J=1.5 Hz, 1H), 7.43 (dd,J=1.9, 0.8 Hz, 1H), 7.29 (d, J=7.9 Hz, 1H), 6.57 (dd, J=3.4, 0.8 Hz,1H), 6.41 (dd, J=3.3, 1.9 Hz, 1H), 5.48 (d, J=1.9 Hz, 2H), 4.93 (s, 2H),4.81 (s, 2H), 4.62 (s, 2H), 3.86 (s, 3H), 3.85 (s, 3H), 3.77 (s, 3H),2.44 (s, 3H), 2.26 (s, 3H), 2.22 (s, 3H), 2.20 (s, 3H) ; LRMS (ESI+):m/z 584.31 (M+H)⁺.

Example 3-4 26091: Methyl2-(((4-methoxy-3,5-dimethylpyridin-2-yl)methyl)amino)-3-pentyl-3,4-dihydroquinazoline-7-carboxylate

Except that amine is replaced by pentan-1-amine, the other reactants andpreparation steps are similar to those described in Example 3-1 toafford the title compound.

¹H NMR (400 MHz, Methanol-d₄) δ 8.14 (s, 1H), 7.79 (d, J=7.9 Hz, 1H),7.39 (d, J=7.9 Hz, 1H), 7.32 (s, 1H), 5.24 (s, 2H), 4.70 (s, 2H), 3.86(s, 3H), 3.81 (s, 3H), 3.64 (t, J=7.8 Hz, 2H), 2.44 (s, 3H), 2.25 (s,3H), 1.76 (p, J=7.9 Hz, 2H), 1.37 (dp, J=11.3, 7.1, 6.2 Hz, 4H),0.96-0.83 (m, 3H); ¹³C NMR (101 MHz, Methanol-d₄) δ 165.84, 165.03,155.04, 152.00, 148.85, 137.27, 130.52, 128.00, 126.46, 125.87, 125.64,124.60, 116.16, 59.47, 51.56, 50.90, 50.56, 47.94, 28.23, 26.36, 22.07,12.93, 12.02, 9.51; LRMS (ESI+): m/z 425.3 (M+H)⁺.

Example 3-5 26092: Methyl2-(((4-methoxy-3,5-dimethylpyridin-2-yl)methyl)amino)-3-(4-methoxybenzyl)-3,4-dihydroquinazoline-7-carboxylate

Except that amine is replaced by (4-methoxyphenyl)methanamine, the otherreactants and preparation steps are similar to those described inExample 3-1 to afford the title compound.

¹H NMR (400 MHz, Methanol-d₄) δ 8.09 (s, 1H), 7.71 (dd, J=7.8, 1.4 Hz,1H), 7.57 (d, J=1.4 Hz, 1H), 7.39 (d, J=8.5 Hz, 2H), 7.31 (d, J=7.8 Hz,1H), 6.92-6.83 (m, 2H), 5.65 (s, 2H), 5.18 (s, 2H), 4.68 (s, 2H), 3.82(s, 3H), 3.79 (s, 3H), 3.74 (s, 3H), 2.43 (s, 3H), 2.18 (s, 3H); LRMS(ESI+): m/z 475.3 (M+H)⁺.

Example 3-6 21110:2-(((4-methoxy-3,5-dimethylpyridin-2-yl)methyl)amino)-3-(3-methoxypropyl)-3,4-dihydroquinazoline-7-carboxylicacid

Except that amine is replaced by 3-methoxypropan-1-amine, the otherreactants and preparation steps are similar to those described inExample 3-7 to afford the title compound.

¹H NMR (400 MHz, Methanol-d₄) δ 7.84 (dd, J=7.9, 1.4 Hz, 1H), 7.64 (s,1H), 7.46 (d, J=1.4 Hz, 1H), 7.40 (d, J=7.9 Hz, 1H), 5.26 (s, 2H), 4.69(s, 2H), 3.85 (s, 3H), 3.75 (t, J=6.9 Hz, 2H), 3.51 (t, J=5.7 Hz, 2H),2.27 (s, 3H), 2.04 (d, J=4.9 Hz, 6H), 1.29 (d, J=3.5 Hz, 2H); LRMS(ESI+): m/z 413.3 (M+H)⁺.

Example 3-7 26089:3-(furan-2-ylmethyl)-2(((4-methoxy-3,5-dimethylpyridin-2-yl)methyl)amino)-3,4-dihydroquinazoline-7-carboxylicacid

To a solution of 4-(bromomethyl)-3-nitrobenzoic acid 1 (5.0 g, 27.0mmol) in dry MeOH/CH₂Cl₂ (3 mL: 30 mL), was added DCC (1.2 equiv) andDMAP (0.005 equiv) and the reaction mixture was stirred at roomtemperature for 16 h. The byproduct DCU was filtered off and crude waspurified by flash column chromatography to get methyl4-(bromomethyl)-3-nitrobenzoate 2 (76%) as an off-white solid.

Compound 2 (4.0 g, 14.5 mmol) and 2-Aminomethylfuran (3 equiv) in dryCH₂Cl₂ (50 mL) were stirred at room temperature for 48 hours. Uponcompletion of reaction the solvent was removed and the crude product waspurified by flash column chromatography to afford nitro benzoate 3(82%).

To a solution of compound 3 (3.65 g, 11.9 mmol) in dry MeOH (100 mL),SnCl₂.2H₂O (3.5 equiv) was added and the resulting reaction mixture wasrefluxed for 10 min. Upon completion of reaction, the byproduct wasfiltered through a bed of celite and filtrate was evaporated. The crudeproduct was portioned between 1 N NaOH and ethyl acetate. The aqueouslayer was extracted with ethyl acetate (3×20 mL) and the combined layerswere dried over MgSO₄ and concentrated under reduced pressure to furnishcompound 4 (87%).

Use DCM to dissolve compound 4 (1.0 g, 3.8 mmol) then add 1.2 equiv.CNBr to react at room temperature. After 8 hours the mixture can beextracted with DCM and water. The solvent was removed and the crudeproduct was purified by flash column chromatography to afford 5 (60%).

To a solution of methyl2-amino-3-(furan-2-ylmethyl)-3,4-dihydroquinazoline-7-carboxylate 5 (0.3g, 1.05 mmol) in acetoniritle (20 mL) was added K₂CO₃ (0.29 g, 2.1 mmol)and KI (0.005 g, 0.03 mmol) followed by2-(chloromethyl)-4-methoxy-3,5-dimethylpyridine 6 (0.722 g, 3.89 mmol)and the reaction mixture was allowed to reflux for six hours. After 24hours, the solvent was evaporated and the reaction mixture was dilutedwith saturated aq. NaHCO₃ (30 mL) and extracted with EtOAc (3*30 mL).

The combined organic phase was washed with saturated brine (30 mL). Thecrude product was purified by silica-gel column chromatography using 8%methanol/EtOAc to obtain Methyl3-(furan-2-ylmethyl)-2-(((4-methoxy-3,5-dimethylpyridin-2-yl)methyl)amino)-3,4-dihydroquinazoline-7-carboxylate7 0.43 g (70%).

And add NaOH (0.198 g, 4.95 mmol) to a solution of methyl3-(furan-2-ylmethyl)-2-(((4-methoxy-3,5-dimethylpyridin-2-yl)methyl)amino)-3,4-dihydroquinazoline-7-carboxylate7 (0.43 g, 0.99 mmol) in the EtOH/H₂O (1/1, 10mL) in the refluxcondition. After 1 hour, the solvent was evaporated and the reactionmixture was diluted with saturated aq. HCl (30 mL) and extracted withEtOAc (3*30 mL). The combined organic phase was washed with saturatedbrine (30 mL). The crude product was purified by silica-gel columnchromatography using 20% methanol/EtOAc to obtain the pure product as awhite solid 0.27 g (65%).

¹H NMR (400 MHz, Methanol-d₄) δ 8.07 (s, 1H), 7.70 (d, J=7.9 Hz, 1H),7.53 (d, J=1.8 Hz, 1H), 7.35 (s, 1H), 7.14 (d, J=7.8 Hz, 1H), 6.57 (d,J=3.2 Hz, 1H), 6.43 (dd, J=3.2, 1.8 Hz, 1H), 5.22 (s, 2H), 4.84 (s, 2H),4.53 (s, 2H), 3.82 (s, 3H), 2.40 (s, 3H), 2.22 (s, 3H); ¹³C NMR (101MHz, Methanol-d₄) δ 171.74, 164.87, 155.39, 151.73, 148.52, 147.49,143.54, 138.56, 136.13, 126.27, 125.93, 124.64, 124.63, 116.56, 110.30,109.86, 59.40, 50.46, 47.46, 46.94, 46.47, 11.97, 9.33; LRMS (ESI+): m/z421.2 (M+H)⁺.

Example 3-8 26090:2-(((4-methoxy-3,5-dimethylpyridin-2-yl)methyl)amino)-3-pentyl-3,4-dihydroquinazoline-7-carboxylicacid

Except that amine is replaced by pentan-1-amine, the other reactants andpreparation steps are similar to those described in Example 3-7 toafford the title compound.

¹H NMR (400 MHz, Methanol-d₄) δ 8.03 (dd, J=8.4, 1.4 Hz, 1H), 7.96 (s,1H), 7.84 (d, J=1.3 Hz, 1H), 7.55 (d, J=8.4 Hz, 1H), 3.83 (s, 3H), 2.41(s, 3H), 2.22 (s, 3H), 1.92-1.83 (m, 2H), 1.43 (tt, J=5.7, 2.8 Hz, 4H),1.29 (d, J=4.0 Hz, 2H), 0.97-0.92 (m, 3H); LRMS (ESI+): m/z 411.3(M+H)⁺.

Example 4-1 NCTU-SUN-12082: Methyl1-(2-(cyclohex-1-en-1-yl)ethyl)-2-(((4-methoxy-3,5-dimethylpyridin-2-yl)methyl)thio)-1H-benzo[d]imidazole-5-carboxylate

To a solution of 4-fluoro-3-nitrobenzoic acid 1, H₂SO₄ (5 mL, 0.3 M) isadded and the reaction mixture is heated to reflux. The solvent isremoved under reduced pressure; crude reaction mixture is dissolved inEtOAc. The EtOAc layer was dried over anhydrous MgSO₄ and evaporated toget methyl 4-fluoro-3-nitrobenzoate 2 as a white solid.

Compound 2 and 2-(cyclohex-1-en-1-yl)ethanamine were stirred at roomtemperature for 2 hours. Upon completion of reaction the solvent wasremoved and the crude product was purified to afford nitro benzoates 3.

To a solution of compound 3, zinc dust and ammonium formate are addedand the resulting reaction mixture is stirred at room temperature. Uponcompletion of reaction, Zn dust is filtered and the filtrate isevaporated and the product is dissolved in CH₂Cl₂. The precipitatedammonium formate was filtered off and the solvent was evaporated tofurnish compound 4.

To the stirred solution of compound 4 is added carbon disulfide and KOHat 50° C. in the ethanol for 8 hours. The mixture can be neutralized byacetic acid and extracted with EtOAc and water. The solvent was removedand the crude product was purified to afford 5.

To a solution of methyl1-(2-(cyclohex-1-en-1-yl)ethyl)-2-thioxo-2,3-dihydro-1H-benzo[d]imidazole-5-carboxylate5 is added K₂CO₃ and KI followed by2-(chloromethyl)-4-methoxy-3,5-dimethylpyridine 6 and the reactionmixture was allowed to reflux. The solvent is evaporated and thereaction mixture is diluted and extracted with EtOAc.

The combined organic phase was washed with saturated brine. The crudeproduct was purified to obtain the pure product NCTU-SUN-12082 as awhite solid 0.053 g (71%).

¹H NMR (300 MHz, Acetone-d₆) δ 8.24 (d, J=1.2 Hz, 1H), 8.20 (s, 1H),7.91 (dd, J=8.5, 1.4 Hz, 1H), 7.53 (d, J=8.5 Hz, 1H), 5.22 (s, 1H), 4.83(s, 2H), 4.28 (t, J=7.0 Hz, 2H), 3.91 (s, 3H), 3.80 (s, 3H), 2.47-2.35(m, 5H), 2.25 (s, 3H), 1.99 (m, 2H), 1.80 (m, 2H), 1.62-1.38 (m, 4H).

Example 4-2 12083:1-(2-(cyclohex-1-en-1-yl)ethyl)-2(((4-methoxy-3,5-dimethylpyridin-2-yl)methyl)thio)-1H-benzo[d]imidazole-5-carboxylicacid

To a solution of 4-fluoro-3-nitrobenzoic acid 1, H₂SO₄ (5 mL, 0.3 M) isadded and the reaction mixture is heated to reflux. The solvent isremoved under reduced pressure; crude reaction mixture is dissolved inEtOAc. The EtOAc layer was dried over anhydrous MgSO₄ and evaporated toget methyl 4-fluoro-3-nitrobenzoate 2 as a white solid.

Compound 2 and 2-(cyclohex-1-en-1-yl)ethanamine were stirred at roomtemperature for 2 h. Upon completion of reaction the solvent was removedand the crude product was purified to afford nitro benzoates 3.

To a solution of compound 3, zinc dust and ammonium formate are addedand the resulting reaction mixture is stirred at room temperature. Uponcompletion of reaction, Zn dust is filtered and the filtrate isevaporated and the product is dissolved in CH₂Cl₂. The precipitatedammonium formate was filtered off and the solvent was evaporated tofurnish compound 4.

To the stirred solution of compound 4 is added carbon disulfide and KOHat 50° C. in the ethanol for 8 hours. The mixture can be neutralized byacetic acid and extracted with EtOAc and water. The solvent was removedand the crude product was purified to afford 5.

To a solution of methyl1-(2-(cyclohex-1-en-1-yl)ethyl)-2-thioxo-2,3-dihydro-1H-benzo[d]imidazole-5-carboxylate5 is added K₂CO₃ and KI followed by2-(chloromethyl)-4-methoxy-3,5-dimethylpyridine 6 and the reactionmixture was allowed to reflux. The solvent is evaporated and thereaction mixture is diluted and extracted with EtOAc.

The combined organic phase was washed with saturated brine. The crudeproduct was purified to obtain Methyl1-(2-(cyclohex-1-en-1-yl)ethyl)-2-(((4-methoxy-3,5-dimethylpyridin-2-yl)methyl)thio)-1H-benzo[d]imidazole-5-carboxylate7 0.053 g (71%).

And add NaOH (0.0251 g, 0.63 mmol) to a solution of Methyl1-(2-(cyclohex-1-en-1-yl)ethyl)-2-(((4-methoxy-3,5-dimethylpyridin-2-yl)methyl)thio)-1H-benzo[d]imidazole-5-carboxylate7 (0.053 g, 0.126 mmol) in the EtOH/H₂O (1/1, 3mL) in the refluxcondition. After 1 hour, the solvent was evaporated and the reactionmixture was diluted with saturated aq. HCl (10 mL) and extracted withEtOAc (3*10 mL). The combined organic phase was washed with saturatedbrine (30 mL). The crude product was purified by silica-gel columnchromatography using 20% methanol/EtOAc to obtain the pure productNCTU-SUN-12083 as a white solid 0.030 g (65%).

¹H NMR (300 MHz, CD₃OD δ 8.30 (d, J=1.4 Hz, 1H), 8.14 (s, 1H), 7.98 (dd,J=8.5, 1.5 Hz, 1H), 7.49 (d, J=8.5 Hz, 1H), 5.51 (s, 2H), 5.08 (s, 1H),4.71 (s, 2H), 4.24 (t, J=6.8 Hz, 2H), 3.79 (s, 3H), 2.44-2.31 (m, 5H),2.27 (s, 3H), 2.04-1.89 (m, 2H), 1.88-1.70 (m, 2H), 1.62-1.39 (m, 4H).

Example 4-3 12084: Methyl1-(2-(cyclohex-1-en-1-yl)ethyl)-2-(((4-methoxy-3,5-dimethylpyridin-2-yl)methyl)sulfinyl)-1H-benzo[d]imidazole-5-carboxylate

To a solution of 4-fluoro-3-nitrobenzoic acid 1, H₂SO₄ (5 mL, 0.3 M) isadded and the reaction mixture is heated to reflux. The solvent isremoved under reduced pressure; crude reaction mixture is dissolved inEtOAc. The EtOAc layer was dried over anhydrous MgSO₄ and evaporated toget methyl 4-fluoro-3-nitrobenzoate 2 as a white solid.

Compound 2 and 2-(cyclohex-1-en-1-yl)ethanamine were stirred at roomtemperature for 2 hours. Upon completion of reaction the solvent wasremoved and the crude product was purified to afford nitro benzoates 3.

To a solution of compound 3, zinc dust and ammonium formate are addedand the resulting reaction mixture is stirred at room temperature. Uponcompletion of reaction, Zn dust is filtered and the filtrate isevaporated and the product is dissolved in CH₂Cl₂. The precipitatedammonium formate was filtered off and the solvent was evaporated tofurnish compound 4.

To the stirred solution of compound 4 is added carbon disulfide and KOHat 50° C. in the ethanol for 8 hours. The mixture can be neutralized byacetic acid and extracted with EtOAc and water. The solvent was removedand the crude product was purified to afford 5.

To a solution of methyl1-(2-(cyclohex-1-en-1-yl)ethyl)-2-thioxo-2,3-dihydro-1H-benzo[d]imidazole-5-carboxylate5 is added K₂CO₃ and KI followed by2-(chloromethyl)-4-methoxy-3,5-dimethylpyridine 6 and the reactionmixture was allowed to reflux. The solvent is evaporated and thereaction mixture is diluted and extracted with EtOAc.

The combined organic phase was washed with saturated brine. The crudeproduct was purified to obtain Methyl1-(2-(cyclohex-1-en-1-yl)ethyl)-2(((4-methoxy-3,5-dimethylpyridin-2-yl)methyl)thio)-1H-benzo[d]imidazole-5-carboxylate7 0.053 g (71%).

And add mCPBA (0.0058 g, 0.034 mmol) to a solution of Methyl1-(2-(cyclohex-1-en-1-yl)ethyl)-2(((4-methoxy-3,5-dimethylpyridin-2-yl)methyl)thio)-1H-benzo[d]imidazole-5-carboxylate7 (0.053 g, 0.0126 mmol) in the DCM/MeOH (9/1, 4.5 mL) in the ice bath.Then, add NaHCO₃ (0.0007 g, 0.0088 mmol) and remove the ice bath. Letthe crude stir at room temperature in 1 hour. The reaction mixture waswashed with DCM (5 mL). The solvent was evaporated and the to obtain thepure product NCTU-SUN-12084 as a white solid 0.030 g (65%).

¹H NMR (300 MHz, CDCl₃) δ 8.55 (s, 1H), 8.13 (s, 1H), 8.10 (dd, J=8.7,1.5 Hz, 1H), 7.43 (d, J=8.8 Hz, 1H), 5.03 (q, J=12.9 Hz, 3H), 4.59-4.35(t, J=8.3 Hz, 2H), 4.58-4.36 (m, 2H), 3.97 (s, 3H), 3.71 (s, 3H), 2.49(t, J=8.3 Hz, 2H), 2.30 (s, 3H), 2.22 (s, 3H), 2.03-1.78 (m, 4H), 1.51(m, 4H).

Example 5-1 12092:2(((4-methoxy-3,5-dimethylpyridin-2-yl)methyl)thio)-1H-benzo[d]imidazol-5-yl(((9H-fluoren-9-yl)methoxy)carbonyl)glycinate

To a solution of 2-thioxo-2,3-dihydro-1H-benzo[d]imidazol-5-yl2-((((9H-fluoren-9-yl)methoxy)carbonyl)amino)acetate 1 (0.08 g, 0.18mmol) in ethanol (9 mL) was added NaOH (0.079 g, 0.198 mmol) followed by2-(chloromethyl)-4-methoxy-3,5-dimethylpyridine 2 (0.367 g, 0.198 mmol)and the reaction mixture was allowed to reflux for one hour. Once thereaction was completed, the solvent was evaporated and the crude productwas purified by silica-gel column chromatography using 2% MeOH/DCM toobtain the pure product NCTU-SUN-12092 as a white solid. 0.31 g, 54.5%.

¹H NMR (300 MHz, Acetone-d₆) δ 8.26 (s, 1H), 7.87 (d, J=7.4 Hz, 2H),7.74 (d, J=7.4 Hz, 2H), 7.51 (d, J=8.6 Hz, 1H), 7.41 (t, J=7.3 Hz, 2H),7.32 (t, J=7.4 Hz, 3H), 7.14 (t, J=6.6 Hz, 1H), 6.95 (dd, J=8.7, 2.1 Hz,1H), 4.67 (s, 2H), 4.40 (d, J=7.3 Hz, 2H), 4.36-4.21 (m, 3H), 3.80 (s,3H), 2.36 (s, 3H), 2.25 (s, 3H).

Example 5-2 12093:2(((4-methoxy-3,5-dimethylpyridin-2-yl)methyl)thio)-1H-benzo[d]imidazol-5-yl(tert-butoxycarbonyl)glycinate

Except that imidazole is replaced by2-thioxo-2,3-dihydro-1H-benzo[d]imidazol-5-yl2-((tert-butoxycarbonyl)amino)acetate, the other reactants andpreparation steps are similar to those described in Example 5-1 toafford the title compound.

¹H NMR (300 MHz, Acetone) δ 8.27 (s, 1H), 7.50 (s, 1H), 7.29 (d, J=2.1Hz, 1H), 6.93 (dd, J=8.6, 2.1 Hz, 1H), 6.50 (s, 1H), 4.67 (s, 2H), 4.12(d, J=6.2 Hz, 2H), 3.81 (s, 3H), 2.38 (s, 3H), 2.26 (s, 3H), 1.45 (s,9H).

Example 5-3 12094:2-(((4-methoxy-3,5-dimethylpyridin-2-yl)methyl)thio)-1Hbenzo[d]-imidazole-5-yl(S)-2-((((9H-fluoren-9-yl)methoxy)carbonyl)amino)-2-phenylacetate

Except that imidazole is replaced by(S)-2-thioxo-2,3-dihydro-1H-benzo[d]imidazol-5-yl2-((((9H-fluoren-9-yl)methoxy)carbonyl)amino)-2-phenylacetate, the otherreactants and preparation steps are similar to those described inExample 5-1 to afford the title compound.

¹H NMR (300 MHz, Acetone-d₆) δ 8.24 (s, 1H), 7.85 (d, J=7.5 Hz, 2H),7.75 (d, J=7.4 Hz, 2H), 7.65 (d, J=7.2 Hz, 2H), 7.52-7.39 (m, 6H), 7.32(m, 2H), 7.22 (d, J=1.6 Hz, 1H), 6.83 (dd, J=9.1, 1.5 Hz, 1H), 5.67 (s,1H), 4.66 (s, 2H), 4.48-4.25 (m, 3H), 2.35 (s, 3H), 2.25 (s, 3H).

Example 6-1 NCTU-SUN-22138:5-methoxy-2-((2-methoxy-3,6-dimethylbenzyl)thio)-1H-benzo[d]imidazole

To a solution of 2-methoxy-1,3,4-trimethylbenzene 1 (0.3 g, 2.00 mmol)in chloroform (30 mL) was added NBS (0.177 g, 1.00 mmol) and in thelight-induced reactions, two Philips “IR 250 W lamps were placed at sucha distance from the reaction flask that reflux was maintained. Once thereaction was completed, the solvent was evaporated and the crude productwas purified by silica-gel column chromatography using hexane to obtainbrominated product 2 0.092 g, 20%.

To a solution of t brominated product 2 (0.1 g, 0.43 mmol) in ethanol (2mL) was added NaOH (0.017 g, 0.43 mmol) followed by2-(chloromethyl)-4-methoxy-3,5-dimethylpyridine 3 (0.071 g, 0.39 mmol)and the reaction mixture was allowed to reflux for one hour. Once thereaction was completed, the solvent was evaporated and the crude productwas purified by silica-gel column chromatography using 2% MeOH/DCM toobtain NCTU-SUN-22138 0.077 g, 60%.

LRMS (ESI+): m/z 329.2 (M+H)⁺

Example 6-2 22141:2-((2-methoxy-3,6-dimethylbenzyl)thio)-1H-benzo[d]imidazol-5-ol

To a solution of 2-methoxy-1,3,4-trimethylbenzene 1 (0.3 g, 2.00 mmol)in chloroform (30 mL) was added NBS (0.177 g, 1.00 mmol) and in thelight-induced reactions, two Philips “IR 250 W lamps were placed at sucha distance from the reaction flask that reflux was maintained. Once thereaction was completed, the solvent was evaporated and the crude productwas purified by silica-gel column chromatography using hexane to obtainbrominated product 2 0.092 g, 20%.

To a solution of t brominated product 2 (0.1 g, 0.43 mmol) in ethanol (2mL) was added NaOH (0.017 g, 0.43 mmol) followed by2-(chloromethyl)-4-hydroxy-3,5-dimethylpyridine 3 (0.071 g, 0.39 mmol)and the reaction mixture was allowed to reflux for one hour. Once thereaction was completed, the solvent was evaporated and the crude productwas purified by silica-gel column chromatography using 2% MeOH/DCM toobtain NCTU-SUN-22138 0.077 g, 60%.

LRMS (ESI+): m/z 315.1 (M+H)⁺

Example 6-3 21133:2((3-(bromomethyl)-2-((tert-butyldimethylsilyl)oxy)-6-methylbenzyl)thio)-5-methoxy-1H-benzo[d]imidazole

To a solution of tert-butyldimethyl(2,3,6-trimethylphenoxy)silane 1 (1.2g, 4.7 mmol) in chloroform (50 mL) was added NBS (1.7 g, 9.5 mmol) andin the light-induced reactions, two Philips “IR 250 W lamps were placedat such a distance from the reaction flask that reflux was maintained.Once the reaction was completed, the solvent was evaporated and thecrude product was purified by silica-gel column chromatography usinghexane to obtain dibrominated product 2 0.31 g, 20%.

To a solution of dibrominated product 2 (0.3 g, 0.90 mmol) in ethanol (9mL) was added NaOH (0.036 g, 0.90 mmol) followed by2-(chloromethyl)-4-methoxy-3,5-dimethylpyridine 3 (0.148 g, 0.82 mmol)and the reaction mixture was allowed to reflux for one hour. Once thereaction was completed, the solvent was evaporated and the crude productwas purified by silica-gel column chromatography using 2% MeOH/DCM toobtain NCTU-SUN-21133 0.23 g, 60%.

¹H NMR (400 MHz, Chloroform-d) δ 7.43 (d, J=8.8 Hz, 1H), 7.16 (s, 1H),7.04 (d, J=2.3 Hz, 1H), 6.82 (d, J=2.3 Hz, 1H), 4.69 (s, 2H), 3.78 (s,4H), 2.22 (s, 3H), 2.13 (s, 4H), 0.98 (s, 9H), 0.09 (s, 6H).

LRMS (ESI+): m/z 507.1 (M+H)⁺

Example 6-422139:5-methoxy-2((2-methoxy-3,6-dimethylbenzyl)sulfinyl)-1H-benzo[d]imidazole

To a solution of 2-methoxy-1,3,4-trimethylbenzene 1 (0.3 g, 2.00 mmol)in chloroform (30 mL) was added NBS (0.177 g, 1.00 mmol) and in thelight-induced reactions, two Philips “IR 250 W lamps were placed at sucha distance from the reaction flask that reflux was maintained. Once thereaction was completed, the solvent was evaporated and the crude productwas purified by silica-gel column chromatography using hexane to obtainbrominated product 2 0.092 g, 20%.

To a solution of t brominated product 2 (0.1 g, 0.43 mmol) in ethanol (2mL) was added NaOH (0.017 g, 0.43 mmol) followed by2-(chloromethyl)-4-methoxy-3,5-dimethylpyridine 3 (0.071 g, 0.39 mmol)and the reaction mixture was allowed to reflux for one hour. Once thereaction was completed, the solvent was evaporated and the crude productwas purified by silica-gel column chromatography using 2% MeOH/DCM toobtain 5-methoxy-2-((2-methoxy-3,6-dimethylbenzyl)thio)-1H-benzo[d]imidazole 3 0.077 g, 60%.

And add mCPBA (0.069 g, 0.40 mmol) to a solution of5-methoxy-2-((2-methoxy-3,6-dimethylbenzyl)thio)-1H-benzo[d]imidazole 3(0.077 g, 0.23 mmol) in the DCM/MeOH (9/1, 10 mL) in the ice bath. Then,add NaHCO₃ (0.013 g, 0.16 mmol) and remove the ice bath. Let the crudestir at room temperature in 1 h. The reaction mixture was washed withDCM (10 mL). The solvent was evaporated and the to obtain the pureproduct as a white solid 0.047 g (65%).

LRMS (ESI+): m/z 345.1 (M+H)⁺

Example 7 DAAO enzymatic assay

The DAAO enzymatic activity assay was modified according to the reportof Oguri et al (Oguri, S., Screening of d-amino acid oxidase inhibitorby a new multi-assay method. Food chemistry 2007, 100 (2), 616). TheDAAO activity was measured by using substrate D-alanine reactionproduced hydrogen peroxide (H₂O₂) to further react with3-(4-hydroxyphenyl) propionic acid (HPPA). The HPPA were oxidized byH₂O₂ and peroxidase to become the fluorogenic dimer which was measuredto represent the activity of DAAO.

For porcine kidney DAO IC50 assay, the DAO substrate was prepared in 50mM D-alanine (dissolved in 0.2 M Tris-HCl buffer, pH 8.3). A 100 μl ofD-alanine solution was mixed with 4 μl (in 100% dimethyl sulfoxide,DMSO) of different concentrations of candidate compounds shown in tablesbelow ranging from 48.83 μM, 97.66 μM, 195.31 μM, 390.63 μM, 781.25 μM,1.56 mM, 3.13 mM, 6.25 mM, 12.50 mM, 25.00 mM, and 50.00 mM, with afinal DMSO concentration of 0.167% in each reaction concentration. 10 μlof D-alanine and candidate compound mixture was incubated with 220 μl ofReaction Master Mix in black 96 well plate at 37° C. for 5 minutes. TheReaction Master Mix contained 110 μl of 5 U/mL porcine kidney DAO(Sigma-Aldrich, USA) solution (dissolved with 0.2 M Tris-HCl buffer, pH8.3), 1.1 mL of 15 U/mL peroxidase solution (dissolved with 0.2 MTris-HCl buffer, pH 8.3), 1.1 mL of 20 mM HPPA solution (dissolved with0.2 M Tris-HCl buffer, pH 8.3), and 22 ml of 2 M Tris-HCl buffer (pH8.3) for 110 reaction assays.

Fluorescence intensity (Fs) was measured at 405 nm by irradiationexcitation at 320 nm. The higher the DAO enzymatic activity was, thehigher the fluorescence intensity. The fluorometric inhibition indicator(Fi) was obtained from the following equation:Fi=(Fs−F_(Drug))/(F_(DMSO)), where the fluorescent drug blank (F_(Drug))was measured in the drug mixture solution (using 0.2 M Tris HCl buffer,pH 8.3, without D-alanine). A DMSO blank (F_(DMSO)) was measured under a100% DMSO solution.

Although FAD is generally included in the reaction mixture in theD-amino acid oxidase assay since it easily dissociates from theholoenzyme, the present method was performed without FAD. The inhibitoryeffect of DAO inhibitors was compared by using inhibitory concentrationsleading to 50% inhibition of DAAO activity (IC₅₀) The IC₅₀ values werecalculated by nonlinear regression model using GraphPad Prism, version 5(GraphPad Software, Inc., La Jolla, Calif.). The results of DAO IC50assay of the candidate compounds of the invention are shown in the tablebelow.

pkDAO Enzymatic Assay IC50 95% Confidence ID M.W. IC50 (uM) Range (uM)CBIO 169.6 0.5827 0.5165 to 0.6573 RS-D7 331.39 1.1850 0.9970 to 1.408 12083 451.5811 366.6000 302.2 to 444.8 21105 583.73 300.8000 223.0 to405.9 26072 583.69 236.4000 211.2 to 264.5 21106 462.59 488.1000 309.4to 769.9 21132 431.15 64.1500 60.86 to 67.61 13084 563.56 181.2000 154.3to 212.8 12122 425.4577 12.5400 11.55 to 13.62 21122 373.1096 21.090016.63 to 26.75 11020 465.13 10.4400 9.549 to 11.40 12124 399.46 11.160010.11 to 12.32 12125 413.49 13.3100 12.26 to 14.44 25016 415.16 13.360012.39 to 14.42 28092 399.13 46.7000 41.85 to 52.10 28094 449.52 21.110019.18 to 23.23 25027 413.1409 21.0000 19.70 to 22.37

Example 8 Cell-Based DAO Assay Neuronal Cell Culture

The SK-N-SH neuroblastoma cell line was purchased from American TypeCulture Collection (ATCC). It was cultured in MEM media(Invitrogen/GIBCO, Rockville, Md.) supplemented with 10% fetal bovineserum, 1× NEAA (Invitrogen/GIBCO) at 37° C. with 5% CO2 in a humidifiedatmosphere. Cells were trypsinized and plated into a black 96-well plate(NUNC No. 237108) at a density of 125,000 cells/well in 50 μl beforecell-based DAO assay.

Cell-Based DAO Assay

The cellular DAO activity assay was using a method modified according tothe report of Brandish et al. (Brandish, P. E., et al., A cell-basedultra-high-throughput screening assay for identifying inhibitors ofD-amino acid oxidase. J Biomol Screen, 2006. 11(5): p. 481-7.). SK-N-SHcells were suspended in assay buffers of HANKS buffer solution(Invitrogen/GIBCO No. 14025-092) with 20 mM HEPES. D-serine of (finalconcentration 50 mM) was added in each well as the substrate for DAOenzyme. The Amplex Red Hydrogen Peroxide/Proxidase Assay Kit (MolecularProbes/Invitrogen, cat. A22188) was used to measure H₂O₂ productionwhich diffused across the cell membrane into the assay medium after DAOreaction. After seeding cells into black 96-well plate (Nunc No. 237108,Denmark), 50 μl of SK-N-SH cells (125,000 cells/well) was mixed with 50μl drug solution (2.5 fold of interesting final concentration) andincubate at 37° C. with 5% CO₂ in a humidified atmosphere for 30minutes. After 30 minutes later, 25 μl of a 5 fold mixture containingD-serine, horseradish peroxidase (HRP), and Amplex Red was added intowells containing 100 μl of cell-drugs mixture and incubated at 37° C.with 5% CO₂ in a humidified atmosphere for 3 hours. The finalconcentration of DMSO is below 1%. The fluorescence signal was thendetected in SpectraMax M2e microplate reader (Molecular Devices, USA)with excitation at 544 nm and emission at 590 nm. The optimized assaybuffer contained a final concentration of 50 mM D-serine, 0.625 unitsHRP, and 50 μM Amplex Red in a 125 μl assay volume. The results of thecell-base DAO assay of the candidate compounds of the invention areshown in the table below.

Cell-base DAO assay SK-N-SH 1.25 * 10{circumflex over ( )}5 cells/well(Drug treated for 3.5 hr) Relative DAO activity normalize Cell-basedIC50 assay to DMSO IC50 95% at Final Conc. IC50 Confidence ID M.W. 100uM 10 uM (uM) Range (uM) CBIO 169.6 0.83 1.00 392.30 281.4 to 547.0RS-D7 331.39 0.69 1.05 141.00 81.07 to 245.1 12083 451.5811 0.48 0.6274.15 27.04 to 203.4 21105 583.73 0.58 0.89 218.80 98.89 to 484.3 26072583.69 0.74 0.87 393.00 215.3 to 717.2 21106 462.59 0.77 1.02 477.60245.5 to 929.2 21132 431.15 0.61 0.94 174.80 137.9 to 221.7 13084 563.560.49 0.71 34.91 21.34 to 57.09 12122 425.4577 0.57 0.98 146.60 106.1 to202.6 21122 373.1096 0.50 0.99 149.40 94.76 to 235.5 11020 465.13 0.670.97 220.90 121.5 to 401.9 12124 399.46 0.36 0.97 107.60 73.47 to 157.612125 413.49 0.50 0.80 122.20 61.25 to 243.7 25016 415.16 0.62 1.00187.60 107.7 to 326.8 28092 399.13 0.58 0.94 136.40 86.51 to 215.1 28094449.52 0.58 1.10 121.50 73.91 to 199.9 25027 413.1409 0.69 1.15 240.20142.0 to 406.3

Example 9 Animal Studies of Potency in Treating Schizophrenia SymptomsDrug Efficacy Screening

The NMDA-receptor antagonist MK-801-induced negative or cognitivedeficits in C57BL/6 mice were in a well-established drug-inducedschizophrenia mouse model and as a useful pharmacological animal modelto identify if the RS-D7, its analog and its prodrug improve thesymptoms through the NMDA receptor.

Animals

All wild-type (WT) mice used in this study were backcrossed onto aC57BL/6J background from the Laboratory Animal Center of National TaiwanUniversity Hospital, and all behavioral examinations were conducted inWT mice. For acclimatizing to laboratory conditions, the mice wereallowed free access to food and water and were housed in groups with a12 hours light-dark cycle in a temperature and humidity controlled roomof the Psychology Department, National Taiwan University. All animalswithin the age of 3 months were housed individually one week beforeexperiment testing with food and water available ad libitum. In thebeginning of the experiments, the mice were handled and weighted dailyat least 1 week before the behavioral experiments. The entire animalprocedures were performed according to protocols approved by the AnimalCare and Use Committee established by the National Taiwan University.

Drug Preparation for Treating Animals

MK-801 was dissolved in saline and administered at a volume of 0.01 ml/gbody weight. RS-D7, Drug 12083 (analog of RS-D7) and was freshlydissolved in 1% CMC to the concentration of 2 mg/ml before usage.Prodrug 28095 was freshly dissolved in NMP:HP-beta-CD:H₂O (5:25:70) tothe concentration of 2 mg/ml before usage. All animals were givenvehicle (saline) or MK-801 (0.2 mg/kg, i.p.) 25 minutes before thebehavioral experiments. Both vehicle (1% CMC or NMP:HP-beta-CD:H₂O) andexperimental groups (RS-D7, Drug 12083 or Prodrug 28095) were treatedafter 5 minutes MK-801 administration with the appropriate dose via P.O.injections (at a volume of 0.01 ml/g body weight).

Behavioral Experiment Procedure

For investigating the treatment effect of RS-D7 for negative andcognitive symptoms, a series of three behavioral tests (run from thefirst to the third week), which included open field, sucrose preferencetest and prepulse inhibition were performed in sequence with a 1-weekinterval between tests.

Open Field

To assess spontaneous locomotor activity, each subject was placed intothe center of an open-field apparatus (25.40*25.40*40.64 cm³, CoulbournInstruments, Whitehall, Pa., USA) under dim lighting condition (60 1×).Motor activity parameters (including total travel distance and traveldistance per 10 minutes) were monitored and recorded over a 60 minutesperiod by using Smart video tracking software (Panlab, Harvardapparatus, US). For comparing the treatment effects of differenttreatment groups, the percentage change of rescue effect onMK-801-induced hyperlocomotion was calculated using the followingformula: %=(rescue effect of drug-MK-801 effect)×100%/MK-801 effect.

Compared with the saline controls, mice exhibit the hyperlocomotion inthe open field after acute MK-801 injection. The injection of 200 and400 mg/kg RS-D7 rescued the MK-801 induced hyperlocomotion in mice.However, the 100 mg/kg RS-D7 did not display the treatment effect. Thisresult suggests that acute RS-D7 injection normalized MK-801-inducedhyperlocomotion as a positive symptom of schizophrenia in the open fieldtest. Drug 12083 alleviated MK-801 induced hyperlocomotion deficits at20 and 40 mg/kg dose. 100 mg/kg Prodrug 28095 alleviated MK-801 inducedhyperlocomotion. In conclusion, compared to the MK-801 group, differentdosages of RS-D7, Drug 12083 and Prodrug 28095 can rescue theMK-801-induced hyperlocomotion. The rescue effects of these drugs onMK-801 induced hyperlocomotion were indicated in FIG. 1.

Sucrose Preference Test

To assess the anhedonia, one of the negative symptoms of schizophrenia,all mice underwent 4-day testing. In the beginning of the sucrosepreference, all mice were deprived of water for 23 hours in all theexperiment from one day before the first day. On the first day, eachmouse was given free access to 2 identical bottles with water for 1hour. Then, the 2 identical bottles were replaced that one filled with1% (wt/vol) sucrose solution and the other with water on the second day.On the third and fourth day, each mouse was received MK-801 and RS-D7treatment before the experiment, and also free accessed to bottles for 1hour. After the experiment, the 2 bottles were weighted to measure the1-hour consumption of sucrose solution and water. The sucrose preferencepercentage (SPP) was calculated using the following formula: %SPP=sucrose solution consumption (g)×100%/[water consumption (g)+sucrosesolution consumption (g)].

Compared with the saline controls, a significant reduction of sucroseintake in the sucrose preference test was observed in testing mice afteracute MK-801 injection. The injection of 100, 200 and 400 mg/kg RS-D7rescued the MK-801 induced anhedonia deficit in mice. 20 mg/kg Drug12083 and 200 mg/kg Prodrug 28095 also normalized MK-801 inducedanhedonia. As a result, different dosages of RS-D7, Drug 12083 andProdrug 28095 rescued the anhedonia after acute MK-801 injection. Therescue effects of these drugs on MK-801 induced anhedonia were indicatedin FIG. 2.

Prepulse Inhibition

To assess the sensorimotor gating function, each mouse was tested withthe SR-LAB startle apparatus (San Diego Instruments, San Diego, Calif.,USA). The background noise was 72 dB during testing. Each session wasinitiated with a 5 minutes acclimatization period followed by 64 trials,consisting of pulse-alone (P-alone) trials, prepulse pulse (pp+P)trials, and no stimulation (nostim) trials. A P-alone trial was a 120 dBwhite noise burst of 40 msec. In the pp+P trials, the 120 dB pulse waspreceded (by 100 msec) by a 20 msec of white noise prepulse burst of 78dB (PP6), 82 dB (PP10), or 90 dB (PP18). The nostim trials consisted ofbackground noise only. The session began and ended with a block of sixpresentations of the P-alone trial. Between these two blocks, the restof the 52 trials were performed pseudorandomly and separated byintertrial intervals of 15 sec on average (varying between 10 and 20sec). PPI was calculated as a percentage of the startle response usingthe formula: % PPI=100×[(P-alone score)−(pp+P score)]/(pulse-alonescore), where the pulse-alone score was the average of the pulse-alonevalues from the in-between block of 52 trials.

Mice with acute MK-801 injection exhibited a profound reduction ofacoustic PPI. However, the injection of 100, 200, and 400 mg/kg RS-D7,20 and 40 mg/kg Drug 12083, and 100 and 200 mg/kg Prodrug 28095significantly alleviated MK-801 induced PPI deficit in these mice. Inother words, Mice displayed a significant reduction of PPI after acuteMK-801 injections and they can be normalized by all dosages of RS-D7,Drug 12083 and Prodrug 28095. The recovery rates of MK-801 induced PPIdeficit were indicated in FIG. 3.

What is claimed is: 1-21. (canceled)
 22. A compound of formula (I),

wherein n is 0 or 1, X is —S—; A is N; R_(a) is —C(═O)OR_(a1); whereinR_(a1) is H or linear or branched C₁₋₁₅alkyl; R_(b) is H, linear orbranched C₁₋₁₅alkyl, linear or branched C₂₋₁₅alkenyl,C₁₋₃alkoxy-C₁₋₁₅alkyl-, -T′-C₃₋₁₀cycloalkyl, -T′-C₃₋₁₀cycloalkenyl,-T′-C₆₋₁₀aryl or -T′-C₅₋₁₀heteroaryl; R_(c) each is independently linearor branched C₁₋₁₅alkyl, linear or branched C₁₋₁₅alkoxyl, hydroxyl group,or —C₁₋₁₀alkylene-Y—C₆₋₁₀heteroaryl wherein —Y— is —CH₂—, —NH—, —O— or—S—; m is an integer from 0 to 4; -T′- is C₁₋₃alkylene orC₂₋₃alkenylene; and wherein the heteroaryl contains at least oneheteroatom, each heteroatom being independently S, N or O; wherein thealkyl, alkenyl, alkoxy, cycloalkyl, aryl, heteroaryl, alkylene andalkenylene are each independently unsubstituted or substituted with atleast one substituent; wherein the substituent is each independently ahalogen, amino, nitro, nitroso, linear or branched C₁₋₁₅ alkyl, orlinear or branched C₁₋₁₅ alkoxy or C₃₋₁₀cycloalkyl; and when R_(b) is H,the tautomers are included, or a pharmaceutically acceptable saltthereof.
 23. The compound of claim 22, wherein n is
 0. 24. The compoundof claim 22, wherein m is an integer from 0 to
 3. 25. The compound ofclaim 22, wherein R_(a) is —C(═O)OH, or —C(═O)OC₁₋₄alkyl.
 26. Thecompound of claim 22, wherein R_(c) each is independently halogen,linear or branched C₁₋₆alkyl, linear or branched C₁₋₆alkoxyl, or—C₁₋₁₀alkenylene-Y—C₆₋₁₀heteroaryl; wherein Y is S and C₆₋₁₀heteroarylis unsubstituted or substituted by C₁₋₁₅alkyl, C₂₋₁₅alkenyl,C₁₋₁₅alkoxy, —OH, —NH₂, —NO₂ or halogen.
 27. The compound of claim 22,which is selected from the group consisting of: 12082: Methyl1-(2-(cyclohex-1-en-1-yl)ethyl)-2-(((4-methoxy-3,5-dimethylpyridin-2-yl)methyl)thio)-1H-benzo[d]imidazole-5-carboxylate12083:1-(2-(cyclohex-1-en-1-yl)ethyl)-2-(((4-methoxy-3,5-dimethylpyridin-2-yl)methyl)thio)-1H-benzo[d]imidazole-5-carboxylicacid, and 12088: methyl2-(((4-methoxy-3,5-dimethylpyridin-2-yl)methyl)thio)-1-octyl-1H-benzo[d]imidazole-5-carboxylate,or a pharmaceutically acceptable salt thereof.
 28. A pharmaceuticalcomposition, comprising a compound of claim
 22. 29. A method ofinhibiting a DAAO, comprising contacting a cell with a compound of claim22.
 30. A method of treating or preventing a disease associated withDAAO inhibition in a subject, which comprises administrating aneffective amount of a compound of claim 22 the subject.
 31. The methodof claim 30, wherein the disease is symptom domains of schizophrenia andschizoaffective disorder, depression, Tourette Syndrome, Post-traumaticstress disorder (PTSD), Obsessive-compulsive disorder (OCD), analgesics,loss of memory and/or cognition associated with neurodegenerativediseases or loss of neuronal function characteristic ofneurodegenerative diseases.
 32. The method of claim 31, wherein thesymptom domains of schizophrenia and schizoaffective disorder includenegative, cognitive, depressive, positive and general psychopathologysymptom domains.
 33. The method of claim 30, wherein the disease is mildcognitive impairment (MCI), Alzheimer's disease, Parkinson's diseaseschizophrenia, pain, ataxia or convulsion.